US6936615B2 - Heteroaryl derivatives and their use as medicaments - Google Patents

Heteroaryl derivatives and their use as medicaments Download PDF

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US6936615B2
US6936615B2 US10/741,310 US74131003A US6936615B2 US 6936615 B2 US6936615 B2 US 6936615B2 US 74131003 A US74131003 A US 74131003A US 6936615 B2 US6936615 B2 US 6936615B2
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Peter Emig
Eckhard Günther
Jürgen Schmidt
Bernd Nickel
Bernhard Kutscher
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Aeterna Zentaris GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/50—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4

Definitions

  • the invention relates to novel heteroaryl derivatives of the formula 1, to their preparation and to their use as medicaments, in particular for treating tumors.
  • novel quinoline derivatives of the formula 1 in which
  • R 4 or a straight-chain or branched (C 1 -C 20 )-alkyl radical which can be saturated or unsaturated, with one to three double and/or triple bonds, and which can be unsubstituted or may optionally be substituted at the same or different Catoms by one, two or more aryl, heteroaryl, halogen, cyano, (C 1 -C 6 )-alkoxycarbonylamino, (C 1 -C 6 )-alkoxy, amino, mono-(C 1 -C 4 )-alkylamino or di-(C 1 -C 4 )alkylamino; a (C 6 -C 14 )-aryl radical, (C 6 -C 14 )-aryl-(C 1 -C 4 )-alkyl radical, or a a (C 2 -C 10 )-heteroaryl or (C 2 -C 10 )-heteroaryl-(C 1 -C 4 )-
  • the compounds of the formula (1) according to the invention which have one or more centers of chirality and which are present as racemates can be separated by methods known per se into their optical isomers, i.e. enantiomers or diastereomers.
  • the separation can be carried out by column separation on chiral phases or by recrystallization from an optically active solvent or using an optically active acid or base or by derivatization with an optically active reagent, such as, for example, an optically active alcohol, and subsequent removal of the radical.
  • the quinoline derivatives of the formula (1) according to the invention can be converted into their salts with inorganic or organic acids, in particular, for pharmaceutical use, into their physiologically acceptable salts.
  • Acids which are suitable for this purpose are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, acetic acid, tartaric acid, malic acid, embonic acid, malonic acid, trifluoroacetic acid or maleic acid.
  • the compounds of the formula (1) according to the invention can, if they contain a sufficiently acidic group, such as a carboxyl group, be converted, if desired, into their salts with inorganic or organic bases, in particular, for pharmaceutical use, into their physiologically acceptable salts.
  • Bases which are suitable for this purpose are, for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, lysine, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
  • quinoline derivatives of the formula 1 are provided in which R, R 1 , R 2 , R 3 , X, Z, P, Q, n and m have the meanings given above and R 4 denotes a straight-chain or branched (C 1 -C 20 )-alkyl radical which can be saturated or unsaturated, with one to three double and/or triple bonds, and which can be unsubstituted or optionally substituted on the same or different Catoms by one, two or more aryl, heteroaryl, halogen, (C 1 -C 6 )-alkoxy, amino, mono-(C—C 4 )-alkylamino or di(C 1 -C 4 )-alkylamino;
  • a phenyl ring or a naphthyl ring each of which can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of straight-chain or branched (C 1 -C 8 )-alkyl, (C 3 -C 7 )-cycloalkyl, halogen, carboxyl, (C 1 -C 8 )-alkoxycarbonyl, straightchain or branched (C 1 -C 6 )-alkyl which is substituted by one or more fluorine atoms, preferably trifluoromethyl, hydroxyl, straight-chain or branched (C 1 -C 8 )-alkoxy, preferably methoxy or ethoxy, where adjacent oxygen atoms may also be linked by (C 1 -C 2 )-alkylene groups, preferably a methylene group, benzyloxy, nitro, amino, mono-(C 1 -C 4 )-alkylamino
  • a 2-, 4-, 5-, 6-, 7-, or 8-quinazolinyl radical or a 2-, 4-, 5-, 6-, 7-, or 8-quinazolinyl-(C 1 -C 4 )-alkyl radical, where the (C 1 -C 4 )-alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of hydrogen, (C 1 -C 6 )-alkyl, halogen or oxo ( ⁇ O), and the or [sic] 2-, 4-, 5-, 6-, 7-, or 8-quinazolinyl radical can- be unsubstituted or mono- to pentasubstituted by the same or different substituents from the group of hydrogen, (C 1 -C 6 )-alkyl, halogen, nitro, amino, mono-(C 1 -C 6 ).alkylamino, di-(C 1 -C 6 )-
  • a 2-, 3-, 5-, 6-, 7-, or 8-quinoxalinyl radical or a 2-, 3-, 5-, 6-, 7-, or 8-quinoxalinyl-(C 1 -C 4 )-alkyl radical, where the (C 1 -C 4 )-alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of (C 1 -C 6 )-alkyl, halogen or oxo ( ⁇ O), and the or [sic] 2-, 3-, 5-, 6-, 7-, or 8-quinoxalinyl radical can be unsubstituted or mono- to pentasubstituted by the same or different substituents from the group of hydrogen, (C 1 -C 6 )-alkyl, halogen, nitro, amino, mono-(C 1 -C 6 )-alkylamino, di-(C 1 -C 6 )-alkylamino
  • a 1-, 4-, 5-, 6-, 7-, or 8-phthalazinyl radical or a 1-, 4-, 5-, 6-, 7-, or 8-phthalazinyl-(C 1 -C 4 )-alkyl radical, where the (C 1 -C 4 )-alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of (C 1 -C 6 )-alkyl, halogen or oxo ( ⁇ O), and the or [sic] 1-, 4-, 5-, 6-, 7-, or 8-phthalazinyl radical can be unsubstituted or mono- to pentasubstituted by the same or different substituents from the group of hydrogen, (C 1 -C 6 )-alkyl, halogen, nitro, amino, mono-(C 1 -C 6 )-alkylamino, di-(C 1 -C 6 )alkylamino, hydroxyl
  • a 2-, 6-, 8- or 9-[9H]-purinyl radical or a 2-, 6-, 8- or 9-[9H]purinyl-(C 4 -C 4 )-alkyl radical
  • the (C 1 -C 4 )-alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of (C 1 -C 6 )-alkyl, halogen or-oxo ( ⁇ O)
  • the 2-, 6-, 8- or 9-[9H]-purinyl radical can be unsubstituted or mono- to trisubstituted by the same or different substituents from the group of hydrogen, (C 1 -C 6 )-alkyl, halogen, nitro, amino, mono-(C 1 -C 6 )-alkylamino, di-(C 1 -C 6 )-alkylamino, hydroxyl, (C 1 -C 6
  • a 2-, 6-, 7- or 8-[7H]-purinyl radical or a 2-, 6-, 7- or 8-[7H]purinyl-(C 1 -C 4 )-alkyl radical
  • the (C 1 -C 4 )-alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of (C 1 -C 6 )-alkyl, halogen or oxo ( ⁇ O)
  • the 2-, 6-, 7- or 8-[7H]-purinyl radical can be unsubstituted or mono- to trisubstituted by the same or different substituents from the group of hydrogen, (C 1 -C 6 )-alkyl, halogen, nitro, amino, mono-(C 1 -C 6 )-alkylamino, di-(C 1 -C 6 )-alkylamino, hydroxyl, (C 1 -C 6
  • a 2-, 3-, 4-, 5- or 6-pyridyl radical where the 2-, 3-, 4-, 5- or 6pyridyl radical can be unsubstituted or mono- to tetrasubstituted by the same or different substituents from the group of hydrogen, (C 1 -C 6 )-alkyl, halogen, nitro, amino, mono-(C 1 -C 6 )-alkylamino, di-(C 1 -C 6 )-alkylamino, hydroxyl, (C 1 -C 6 )-alkoxy, benzyloxy, carboxyl, (C 1 -C 6 )-alkoxycarbonyl, (C 1 -C 6 )-alkoxycarbonylamino or (C 1 -C 6 )-alkyl which is mono- or polysubstituted by fluorine, preferably trifluoromethyl, (C 6 -C 10 )-aryl and (C 6 -C 10 )-aryl
  • a 2-, 3-, 4-, 5- or 6-pyridinyl-(C 1 -C 6 )-alkyl radical where the (C 1 -C 6 )-alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of (C 1 -C 6 )alkyl, halogen or oxo ( ⁇ O), and the 2-, 3-, 4-, 5- or 6-pyridinyl radical can be unsubstituted or mono- to tetrasubstituted by the same or different substituents from the group of hydrogen, (C 1 -C 6 )-alkyl, halogen, nitro, amino, mono-(C 1 -C 6 )-alkylamino, di-(C 1 -C 6 ) alkylamino, hydroxyl, (C 1 -C 6 )-alkoxy, benzyloxy, carboxyl, (C 1 -C 6 )-alkoxycarbon
  • a 2-, 4-, or 5-thiazolyl radical or a 2-, 4-, or 5-thiazolyl-(C 1 -C 6 )-alkyl radical
  • the (C 1 -C 6 )-alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of (C 1 -C 6 )-alkyl, halogen or oxo ( ⁇ O)
  • the 2-, 4-, or 5thiazolyl radical can be unsubstituted or mono- or disubstituted by the same or different substituents from the group of hydrogen, (C 1 -C 6 )-alkyl, halogen, nitro, amino, mono-(C 1 -C 6 )-alkylamino, di-(C 1 -C 6 )-alkylamino, hydroxyl, (C 1 -C 6 )-alkoxy, benzyloxy, carboxyl, (C 1 -C 6
  • a 2-, 4-, 5-, 6-, or 7-benzothiazolyl radical or a 2-, 4-, 5-, 6-, or 7 benzothiazolyl-(C 1 -C 6 )-alkyl radical, where the (C 1 -C 6 )-alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of (C 1 -C 6 )-alkyl, halogen or oxo ( ⁇ O), and the 2-, 4-, 5-, 6-, or 7-benzothiazolyl radical can be unsubstituted or mono- to tetrasubstituted by the same or different substituents from the group of hydrogen, (C 1 -C 6 )-alkyl, halogen, nitro, amino, mono-(C 1 -C 6 )-alkylamino, di-(C 1 -C 6 )-alkylamino, hydroxyl, (C 1 -C 6 )
  • a 1-, 2-, 4-, or 5-imidazolyl radical or a 1-, 2-, 4-, or 5-imidazolyl(C 1 -C 6 )-alkyl radical, where the (C 1 -C 6 )-alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of (C 1 -C 6 )-alkyl, halogen or oxo ( ⁇ O), and the 1-, 2-, 4-, or 5-imidazolyl radical can be unsubstituted or mono- to trisubstituted by the same or different substituents from the group of hydrogen, (C 1 -C 6 )-alkyl, halogen, nitro, amino, mono-(C 1 -C 6 )-alkylamino, di-(C 1 -C 6 )-alkylamino, hydroxyl, (C 1 -C 6 )-alkoxy, benzyloxy, carboxyl,
  • a 1- or 5-[1H]-tetrazolyl radical or a 1-, or 5-[1H]-tetrazolyl-(C 1 -C 6 )-alkyl radical
  • the (C 1 -C 6 )-alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of (C 1 -C 6 )-alkyl, halogen or oxo ( ⁇ O)
  • the 1-, or 5-[1H]-tetrazolyl radical can be unsubstituted or substituted by hydrogen, (C 1 -C 6 )-alkyl, halogen, nitro, amino, mono-(C 1 -C 6 )-alkylamino, di-(C 1 -C 6 )-alkylamino, hydroxyl, (C 1 -C 6 )alkoxy, benzyloxy, carboxyl, (C 1 -C 6 )-alk
  • a 2- or 5-[2H]-tetrazoyl radical or a 2- or 5-[2H]-tetrazolyl-(C 1 -C 6 ) alkyl radical
  • the (C 1 -C 6 )-alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of (C 1 -C 6 )-alkyl, halogen or oxo ( ⁇ O)
  • the 2- or 5[2H]-tetrazolyl radical can be unsubstituted or substituted by hydrogen, (C 1 -C 6 )-alkyl, halogen, nitro, amino, mono-(C 1 -C 6 )alkylamino, di-(C 1 -C 6 )-alkylamino, hydroxyl, (C 1 -C 6 )-alkoxy, benzyloxy, carboxyl, (C 1 -C 6 )-alkoxycarbon
  • quinoline derivatives of the formula (1) are provided which are characterized in that R, R, R 2 , R 3 , X, Z, P, Q, n and m have the meanings given above and R4 represents phenyl which is unsubstituted or substituted by one to five the same or different (C 1 -C 6 )-alkoxy groups, where adjacent oxygen atoms may also be linked by (C 1 -C 2 )-alkylene groups.
  • quinoline derivatives of the formula (1) are provided which are characterized in that R, R, R 2 , R 3 , X, Z, P, Q, n and m have the meanings given above and R 4 represents 3,5 dimethoxyphenyl.
  • quinoline derivatives of the formula (1) are provided which are characterized in that R 4 has the meanings given above, R, R 1 , R 2 , R 3 each represent a hydrogen atom, Z represents an oxygen atom and X represents a nitrogen atom, P and Q each represent two hydrogen atoms (i.e. —CH 2 —), m is zero and n is the integer 2.
  • quinoline derivatives of the 20 formula (1) are provided which are characterized in that R, R 1 , R 2 , R 3 each represent a hydrogen atom, Z represents an oxygen atom, X represents a nitrogen atom, P and Q each represent two hydrogen atoms (i.e. —CH2-), m is zero, n represents the integer 2 and R 4 represents a 3,5-dimethoxyphenyl radical.
  • a process for preparing quinoline derivatives of the formula (1) which is characterized in that a quinoline carboxylic acid of the formula (2)
  • R, R 1 , R 2 , R 3 have the meanings given above
  • Z denotes an oxygen or sulfur atom
  • Y represents a leaving group such as halogen, hydroxyl, (C 1 -C 6 )-alkoxy, preferably methoxy or ethoxy, -0-tosyl, -0mesyl or imidazolyl, is reacted with an amine of the formula (3)
  • R 4 , X, P, Q, m and n are as defined above, using, if appropriate, diluents and auxiliaries, and the desired quinoline derivatives are formed.
  • the starting materials (2) and (3) are either commercially available or can be prepared by procedures known per se.
  • the starting materials (2) and (3) are useful intermediates for preparing the quinoline derivatives of the formula (1) according to the invention.
  • reaction temperature and reaction time are known to the person skilled in the art owing to his expert knowledge.
  • the quinoline derivatives of the formula (1) according to the invention are suitable as medicaments, in particular as antitumor agents, for treating mammals, in particular man, but also domestic animals such as horses, cattle, dogs, cats, hares, sheep, poultry and the like.
  • a method for controlling tumors in mammals which is characterized in that at least one quinoline derivative of the formula (1) is administered to a mammal in an amount effective for the treatment of the tumor.
  • the therapeutically effective dose of the quinoline derivative according to the invention in question which is to be administered for the treatment depends inter alia on the nature and the stage of the oncosis, the age and the sex of the patient, the type of administration and the duration of the treatment. Administration can take place orally, rectally, buccally (for example sublingually), parenterally (for example subcutaneously, intramuscularly, intradermally or intravenously), topically or transdermally.
  • medicaments for the treatment of tumors are provided which are characterized in that they comprise, as active ingredient, at least one quinoline derivative according to any of claims 1 to 4 or a pharmaceutically acceptable salt thereof, if appropriate together with customary pharmaceutically acceptable auxiliaries, additives and carriers.
  • These can be solid, semisolid, liquid or aerosol preparations.
  • Suitable solid preparations are, for example, capsules, powders, granules, tablets.
  • Suitable semisolid preparations are, for example, ointments, creams, gels, pastes, suspensions, oil-in-water and water-in-oil emulsions.
  • Suitable liquid preparations are, for example, sterile aqueous preparations for parenteral administration which are isotonic with the blood of the patient.
  • the cell lines used are the human cervical carcinoma cell lines KB/HeLa (ATCC/CCL17), the murine lymphocyte leukaemia L1210 (ATCC CCL-219), the human breast adenocarcinoma line MCF7/ATCC HTB22) and the ovary adenocarcinoma line SKOV-3 (ATCC HTB77). These are established cell lines which are very well characterized and were obtained from ATCC and cultured.
  • the adherent cells are detached using trypsine/EDTA and pelleted by centrifugation.
  • the cell pellet is then resuspended in RPMI culture medium at the appropriate cell count and transferred to a 96-well microtitre plate.
  • the plates are then cultivated overnight in the incubator with gas inlet.
  • the test substances are made up as stock solutions in DMSO and, on Test Day 2, diluted with culture medium to the desired concentrations.
  • the substances in the culture medium are then added to the cells and incubated in the incubator with gas inlet for 45 h. Cells which have not been treated with test substance serve as control.
  • XTT sodium 3′-[1-(phenylaminocarbonyl)-3,4-tetrazolium]-bis(4-methoxy-6-nitro)benzenesulfonic acid
  • RPMI-1640 medium without Phenol Red
  • PMS N-methyldibenzopyrazine methyl sulfate
  • PBS phosphate-buffered saline
  • the XTT solution is mixed with the PMS solution in a ratio of 50:1 (v/v) shortly before use.
  • the cell plates are then incubated in the incubator with gas inlet for a further 3 h, and the optical density (OD 490nm ) is determined in a photometer.
  • the inhibition in percent relative to the control is calculated.
  • the antiproliferative activity is estimated using regression analysis.

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Abstract

The invention relates to novel quinoline derivatives of the formula 1, to their preparation and to their use as medicaments, in particular for treating tumors.
Figure US06936615-20050830-C00001

Description

RELATED APPLICATION
This application is a continuation of co-pending application Ser. No. 09/910,141 filed Jul. 20, 2001.
FIELD OF THE INVENTION
The invention relates to novel heteroaryl derivatives of the formula 1, to their preparation and to their use as medicaments, in particular for treating tumors.
DESCRIPTION OF THE INVENTION
According to one aspect of the invention, novel quinoline derivatives of the formula 1
Figure US06936615-20050830-C00002
in which
  • R, R1, R2, R3; can be attached to any of the quinoline carbon atoms C2 to C8, are the same or different and independently of one another denote hydrogen, straight-chain or branched (C1-C8)-alkyl, (C3-C1)-cycloalkyl, straight-chain or branched (C1-C8)-alkylcarbonyl, preferably acetyl, straight-chain or branched (C1-C8)-alkoxy, halogen, aryl-(C1-C8)-alkoxy, preferably benzyloxy or phenylethyloxy, nitro, amino, mono-(C1-C4) alkylamino, di-(C1-C4)-alkylamino, (C1-C8) alkoxycarbonylamino, (C1-C6)-alkoxycarbonylamino-(C1-C8)alkyl, cyano, straight-chain or branched cyano-(C1-C6)-alkyl, carboxyl, (C1-C8)-alkoxycarbonyl, (C1-C4)-alkyl which is substituted by one or more fluorine atoms, preferably the trifluoromethyl group, carboxy-(C1-C8)-alkyl or (C1-C8)-alkoxycarbonyl-(C1-C6)-alkyl, (C2-C6)-alkenyl, preferably allyl, (C2-C6)-alkynyl, preferably ethynyl or propargyl, straight-chain or branched cyano-(C1-C6)-alkyl, preferably cyanomethyl, aryl, where the aryl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of halogen, straight-chain or branched (C1-C8)-alkyl, (C3-C1)-cycloalkyl, carboxyl, straightchain or branched (C1-C8)-alkoxycarbonyl, preferably tertbutoxycarbonyl, by trifluoromethyl, hydroxyl, straight-chain or branched (C1-C8)-alkoxy, preferably methoxy or ethoxy, benzyloxy, nitro, amino, mono-(C1-C4)-alkylamino, di-(C1-C4)-alkylamino, cyano, straight-chain or branched cyano-(C1-C6)-alkyl, where additionally R and R1 or R2 and R3 may form a fused aromatic 6-membered ring with the quinoline ring forming an acridine ring which for its part can be substituted at any Catom ring position by the radicals R, R1, R2 and R; having the meanings mentioned above;
  • Z is oxygen or sulfur, where the radical
    Figure US06936615-20050830-C00003
    substituted on the quinoline heterocycle can be attached to Catoms C2-C8 of the quinoline ring skeleton;
  • P, Q independently of one another represent oxygen or in each case two hydrogen atoms (i.e. —CH2—);
  • X is nitrogen or C—R5, where R5 represents hydrogen or (C1-C6)-alkyl;
  • n,m independently of one another denotes an integer between 0-3, with the proviso that in the case n=0, X denotes a CR5R6 group where R5 and R6 independently of one another represent hydrogen or (C1-C6)-alkyl and that the nitrogen atom adjacent to the C=Z group is substituted by a hydrogen atom or a (C1-C6)-alkyl group;
R4 or a straight-chain or branched (C1-C20)-alkyl radical which can be saturated or unsaturated, with one to three double and/or triple bonds, and which can be unsubstituted or may optionally be substituted at the same or different Catoms by one, two or more aryl, heteroaryl, halogen, cyano, (C1-C6)-alkoxycarbonylamino, (C1-C6)-alkoxy, amino, mono-(C1-C4)-alkylamino or di-(C1-C4)alkylamino; a (C6-C14)-aryl radical, (C6-C14)-aryl-(C1-C4)-alkyl radical, or a a (C2-C10)-heteroaryl or (C2-C10)-heteroaryl-(C1-C4)-alkyl radical which contains one or more heteroatoms selected from the group of N, 0 and S, where the (C1-C4)-alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of (C1-C6)-alkyl, halogen or oxo (═O), and where the (C6-C14)-aryl or (C2-C10)-heteroaryl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of straight-chain or branched (C1-C8)alkyl, (C3-C7)-cycloalkyl, halogen, cyano, (C1-C6)alkoxycarbonylamino, (C1-C6)-alkoxy, carboxyl, (C1-C8)-alkoxycarbonyl, straight-chain or branched (C1-C6)-alkyl which is substituted by one or more fluorine atoms, preferably trifluoromethyl, hydroxyl, straight-chain or branched (C1-C8)alkoxy, preferably methoxy or ethoxy, where adjacent oxygen atoms may also be linked by (C1-C2)-alkylene groups, preferably by a methylene group, benzyloxy, nitro, amino, mono-(C1-C4)alkylamino, di-(C1-C4)-alkylamino, aryl, which for its part can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of straight-chain or branched (C1-C8)-alkyl, (C3-C1)-cycloalkyl, carboxyl, straight-chain or branched (C1-C8)-alkoxycarbonyl, by trifluoromethyl, hydroxyl, straight-chain or branched (C1-C8)-alkoxy, preferably methoxy or ethoxy, benzyloxy, nitro, amino, mono-(C1-C4)-alkylamino, di-(C1-C4)-alkylamino, cyano, straight-chain or branched cyano-(C1-C6)-alkyl;
and their structural isomers and stereoisomers, in particular tautomers, diastereomers and enantiomers, and their pharmaceutically acceptable salts, in particular acid addition salts, are provided.
Thus, for example, the compounds of the formula (1) according to the invention which have one or more centers of chirality and which are present as racemates can be separated by methods known per se into their optical isomers, i.e. enantiomers or diastereomers. The separation can be carried out by column separation on chiral phases or by recrystallization from an optically active solvent or using an optically active acid or base or by derivatization with an optically active reagent, such as, for example, an optically active alcohol, and subsequent removal of the radical.
Furthermore, the quinoline derivatives of the formula (1) according to the invention can be converted into their salts with inorganic or organic acids, in particular, for pharmaceutical use, into their physiologically acceptable salts. Acids which are suitable for this purpose are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, acetic acid, tartaric acid, malic acid, embonic acid, malonic acid, trifluoroacetic acid or maleic acid.
Moreover, the compounds of the formula (1) according to the invention can, if they contain a sufficiently acidic group, such as a carboxyl group, be converted, if desired, into their salts with inorganic or organic bases, in particular, for pharmaceutical use, into their physiologically acceptable salts. Bases which are suitable for this purpose are, for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, lysine, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
According to a preferred embodiment, quinoline derivatives of the formula 1 are provided in which R, R1, R2, R3, X, Z, P, Q, n and m have the meanings given above and R4 denotes a straight-chain or branched (C1-C20)-alkyl radical which can be saturated or unsaturated, with one to three double and/or triple bonds, and which can be unsubstituted or optionally substituted on the same or different Catoms by one, two or more aryl, heteroaryl, halogen, (C1-C6)-alkoxy, amino, mono-(C—C4)-alkylamino or di(C1-C4)-alkylamino;
a phenyl ring or a naphthyl ring, each of which can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of straight-chain or branched (C1-C8)-alkyl, (C3-C7)-cycloalkyl, halogen, carboxyl, (C1-C8)-alkoxycarbonyl, straightchain or branched (C1-C6)-alkyl which is substituted by one or more fluorine atoms, preferably trifluoromethyl, hydroxyl, straight-chain or branched (C1-C8)-alkoxy, preferably methoxy or ethoxy, where adjacent oxygen atoms may also be linked by (C1-C2)-alkylene groups, preferably a methylene group, benzyloxy, nitro, amino, mono-(C1-C4)-alkylamino, di-(C1-C4)-alkylamino, aryl, which for its part can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of straight-chain or branched (C1-C8)-alkyl, (C3-C1)-cycloalkyl, carboxyl, straight-chain or branched (C1-C8)-alkoxycarbonyl, by trifluoromethyl, hydroxyl, straight-chain or branched (C1-C8)-alkoxy, preferably methoxy or ethoxy, benzyloxy, nitro, amino, mono-(C1-C4)-alkylamino, di-(C1-C4)-alkylamino, cyano, straight-chain or branched cyano-(C1-C6)alkyl;
a 2-, 4-, 5- or 6-pyrimidinyl radical, or a 2-, 4-, 5- or 6-pyrimidinyl(C1-C4)-alkyl radical, where the (C1-C4)-alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of (C1-C6)-alkyl, halogen or oxo (═O), and the 2-, 4-, 5- or 6-pyrimidinyl radical can be unsubstituted or mono- to trisubstituted by the same or different substituents from the group of hydrogen, (C1-C6)-alkyl, halogen, nitro, amino, mono-(C1-C6)-alkylamino, di-(C1-C6)-alkylamino, hydroxyl, (C1-C6)-alkoxy, benzyloxy, carboxyl, (C1-C6)-alkoxycarbonyl, (C1-C6)-alkoxycarbonylamino or (C1-C6)-alkyl which is mono- or polysubstituted by fluorine, preferably trifluoromethyl, (C6-C10)-aryl and (C6-C10)-aryl-(C1-C6)-alkyl;
a 3-, 4-, 5- or 6-pyridazinyl radical, or a 3-, 4-, 5- or 6-pyridazinyl(C1-C4)-alkyl radical, where the (C1-C4)-alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of (C1-C6)-alkyl, halogen or oxo (═O), and the 3-, 4-, 5- or 6-pyridazinyl radical can be unsubstituted or mono- to trisubstituted by the same or different substituents from the group of hydrogen, (C1-C6)-alkyl, halogen, nitro, amino, mono-(C1-C6)-alkylamino, di-(C1-C6)-alkylamino, hydroxyl, (C1-C6)-alkoxy, benzyloxy, carboxyl, (C1-C6)-alkoxycarbonyl, (C1-C6)-alkoxycarbonylamino or (C1-C6)-alkyl which is mono- or polysubstituted by fluorine, preferably trifluoromethyl, (C6-C10)-aryl and (C6-C10)-aryl-(C1-C6)-alkyl;
a 2-, 3-, 5- or 6-pyrazinyl radical, or a 2-, 3-, 5- or 6-pyrazinyl-(C1-C4)-alkyl radical, where the (C1-C4)-alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of (C1-C6)-alkyl, halogen or oxo (═O), and the 2-, 3-, 5- or 6-pyrazinyl radical can be unsubstituted or mono- to trisubstituted by the same or different substituents from the group of hydrogen, (C1-C6)-alkyl, halogen, nitro, amino, mono-(C1-C6)-alkylamino, di-(C1-C6)-alkylamino, hydroxyl, (C1-C6)-alkoxy, benzyloxy, carboxyl, (C1-C6)-alkoxycarbonyl, (C1-C6)alkoxycarbonylamino or (C1-C6)-alkyl which is mono- or polysubstituted by fluorine, preferably trifluoromethyl, (C6-C10)-aryl and (C6-C10)-aryl-(C1-C6)-alkyl;
a 3-, 4-, 5-, 6-, 7-, or 8-cinnolinyl radical, or a 3-, 4-, 5-, 6-, 7-, or 8cinnolinyl-(C1-C4)-alkyl radical, where the (C1-C4)-alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of (C1-C6)-alkyl, halogen or oxo (═O), and the 3-, 4-, 5-, 6-, 7-, or 8-cinnolinyl radical can be unsubstituted or mono- to pentasubstituted by the same or different substituents from the group of hydrogen, (C1-C6)-alkyl, halogen, nitro, amino, mono-(C1-C6)-alkylamino, di-(C1-C6)-alkylamino, hydroxyl, (C1-C6)-alkoxy, benzyloxy, carboxyl, (C1-C6)-alkoxycarbonyl, (C1-C6)-alkoxycarbonylamino or (C1-C6)-,alkyl which is mono- or polysubstituted by fluorine, preferably trifluoromethyl, (C6-C10)-aryl and (C6-C10)-aryl-(C1-C6)-alkyl;
a 2-, 4-, 5-, 6-, 7-, or 8-quinazolinyl radical, or a 2-, 4-, 5-, 6-, 7-, or 8-quinazolinyl-(C1-C4)-alkyl radical, where the (C1-C4)-alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of hydrogen, (C1-C6)-alkyl, halogen or oxo (═O), and the or [sic] 2-, 4-, 5-, 6-, 7-, or 8-quinazolinyl radical can- be unsubstituted or mono- to pentasubstituted by the same or different substituents from the group of hydrogen, (C1-C6)-alkyl, halogen, nitro, amino, mono-(C1-C6).alkylamino, di-(C1-C6)-alkylamino, hydroxyl, (C1-C6)-alkoxy, benzyloxy, carboxyl, (C1-C6)-alkoxycarbonyl, (C1-C6)-alkoxycarbonylamino or (C1-C6)-alkyl which is mono- or polysubstituted by fluorine, preferably trifluoromethyl, (C6-C10)-aryl and (C6-C10)-aryl-(C1-C6)-alkyl;
a 2-, 3-, 5-, 6-, 7-, or 8-quinoxalinyl radical, or a 2-, 3-, 5-, 6-, 7-, or 8-quinoxalinyl-(C1-C4)-alkyl radical, where the (C1-C4)-alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of (C1-C6)-alkyl, halogen or oxo (═O), and the or [sic] 2-, 3-, 5-, 6-, 7-, or 8-quinoxalinyl radical can be unsubstituted or mono- to pentasubstituted by the same or different substituents from the group of hydrogen, (C1-C6)-alkyl, halogen, nitro, amino, mono-(C1-C6)-alkylamino, di-(C1-C6)-alkylamino, hydroxyl, (C1-C6)-alkoxy, benzyloxy, carboxyl, (C1-C6)-5 alkoxycarbonyl, (C1-C6)-alkoxycarbonylamino or (C1-C6)-alkyl which is mono- or polysubstituted by fluorine, preferably trifluoromethyl, (C6-C10)-aryl and (C6-C10)-aryl-(C1-C6)-alkyl;
a 1-, 4-, 5-, 6-, 7-, or 8-phthalazinyl radical, or a 1-, 4-, 5-, 6-, 7-, or 8-phthalazinyl-(C1-C4)-alkyl radical, where the (C1-C4)-alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of (C1-C6)-alkyl, halogen or oxo (═O), and the or [sic] 1-, 4-, 5-, 6-, 7-, or 8-phthalazinyl radical can be unsubstituted or mono- to pentasubstituted by the same or different substituents from the group of hydrogen, (C1-C6)-alkyl, halogen, nitro, amino, mono-(C1-C6)-alkylamino, di-(C1-C6)alkylamino, hydroxyl, (C1-C6)-alkoxy, benzyloxy, carboxyl, (C1-C6)alkoxycarbonyl, (C1-C6)-alkoxycarbonylamino or (C1-C6)-alkyl which is mono- or polysubstituted by fluorine, preferably trifluoromethyl, (C6-C10)-aryl and (C6-C10)-aryl-(C1-C6)-alkyl;
a 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl radical, or a 2-, 3-, 4-, 5-, 6-, 7 or 8-quinolyl-(C1-C4)-alkyl radical, where the (C1-C4)-alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of (C1-C6)-alkyl, halogen or oxo (═O), and the 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl radical can be unsubstituted or -mono- to hexasubstituted by the same or different substituents from the group of hydrogen, (C1-C6)-alkyl, preferably methyl, particularly preferably 2-methyl, halogen, nitro, amino, mono-(C1-C6)-alkylamino, di-(C1-C6)-alkylamino, hydroxyl, (C1-C6)-alkoxy, benzyloxy, carboxyl, (C1-C6)-alkoxycarbonyl, (C1-C6)-alkoxycarbonylamino or (C1-C6)-alkyl which is mono- or polysubstituted by fluorine, preferably trifluoromethyl, (C6-C10)-aryl 10 and (C6-C10)-aryl-(C1-C6)-alkyl;
a 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl radical, or a 1-, 3-, 4-, 5-, 6-, 7 or 8-isoquinolyl-(C1-C4)-alkyl radical, where the (C1-C4)-alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of (C1-C6)-alkyl, halogen or oxo (═O), and the 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl radical can be unsubstituted or mono- to hexasubstituted by the same or different substituents from the group of hydrogen, (C1-C6)-alkyl, halogen, nitro, amino, mono-(C1-C6)-alkylamino, di-(C1-C6)-alkylamino, hydroxyl, (C1-C6)-alkoxy, benzyloxy, carboxyl, (C1-C6) alkoxycarbonyl, (C1-C6)-alkoxycarbonylamino or (C1-C6)-alkyl which is mono- or polysubstituted by fluorine, preferably trifluoromethyl, (C6-C10)-aryl and (C6-C10)-aryl-(C1-C6)-alkyl;
a 2-, 6-, 8- or 9-[9H]-purinyl radical, or a 2-, 6-, 8- or 9-[9H]purinyl-(C4-C4)-alkyl radical, where the (C1-C4)-alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of (C1-C6)-alkyl, halogen or-oxo (═O), and the 2-, 6-, 8- or 9-[9H]-purinyl radical can be unsubstituted or mono- to trisubstituted by the same or different substituents from the group of hydrogen, (C1-C6)-alkyl, halogen, nitro, amino, mono-(C1-C6)-alkylamino, di-(C1-C6)-alkylamino, hydroxyl, (C1-C6)-alkoxy, benzyloxy, carboxyl, (C1-C6)-alkoxycarbonyl, (C1-C6) alkoxycarbonylamino or (C1-C6)-alkyl which is mono- or polysubstituted by fluorine, preferably trifluoromethyl, (C6-C10)-aryl and (C6-C10)-aryl-(C1-C6)-alkyl;
a 2-, 6-, 7- or 8-[7H]-purinyl radical, or a 2-, 6-, 7- or 8-[7H]purinyl-(C1-C4)-alkyl radical, where the (C1-C4)-alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of (C1-C6)-alkyl, halogen or oxo (═O), and the 2-, 6-, 7- or 8-[7H]-purinyl radical can be unsubstituted or mono- to trisubstituted by the same or different substituents from the group of hydrogen, (C1-C6)-alkyl, halogen, nitro, amino, mono-(C1-C6)-alkylamino, di-(C1-C6)-alkylamino, hydroxyl, (C1-C6)-alkoxy, benzyloxy, carboxyl, (C1-C6)-alkoxycarbonyl, (C1-C6 alkoxycarbonylamino or (C1-C6)-alkyl which is mono- or polysubstituted by fluorine, preferably trifluoromethyl, (C6-C10)-aryl and (C6-C10)-aryl-(C1-C6)-alkyl;
a 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl radical, or a 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl-(C1-C4)-alkyl radical, where the (C1-C6)-alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of (C1-C6)-alkyl, halogen or oxo (═O), and the 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9acridinyl radical can be unsubstituted or mono- to octasubstituted by the same or different substituents from the group of hydrogen, (C1-C6)-alkyl, halogen, nitro, amino, mono-(C1-C6)-alkylamino, di-(C1-C6)-alkylamino, hydroxyl, (C1-C6)-alkoxy, benzyloxy, carboxyl, (C1-C6)-alkoxycarbonyl, (C1-C6)-alkoxycarbonylamino or (C1-C6)-alkyl which is mono- or polysubstituted by fluorine, preferably trifluoromethyl, (C6-C10)-aryl and (C6-C10)-aryl-(C1-C6)-alkyl;
a 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-phenanthridinyl radical, or a 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-phenanthridinyl-(C1-C6)-alkyl radical, where the (C1-C6)-alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of hydrogen, (C1-C6)-alkyl, halogen or oxo (═O), and the 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-phenanthridinyl radical can be unsubstituted or mono- to octasubstituted by the same or different substituents from the group of (C1-C6)-alkyl, halogen, nitro, amino, mono-(C1-C6)-alkylamino, di-(C1-C6)-alkylamino, hydroxyl, (C1-C6)-alkoxy, (C6-C10)-aryl-(C1-C6)-alkoxy, preferably benzyloxy, carboxyl, (C1-C6)-alkoxycarbonyl, (C1-C6)-alkoxycarbonylamino or (C1-C6)-alkyl which is mono- or polysubstituted by fluorine, preferably trifluoromethyl, (C6-C10)-aryl and (C6-C10)-aryl-(C1-C6)-alkyl;
a 2-, 3-, 4-, 5- or 6-pyridyl radical where the 2-, 3-, 4-, 5- or 6pyridyl radical can be unsubstituted or mono- to tetrasubstituted by the same or different substituents from the group of hydrogen, (C1-C6)-alkyl, halogen, nitro, amino, mono-(C1-C6)-alkylamino, di-(C1-C6)-alkylamino, hydroxyl, (C1-C6)-alkoxy, benzyloxy, carboxyl, (C1-C6)-alkoxycarbonyl, (C1-C6)-alkoxycarbonylamino or (C1-C6)-alkyl which is mono- or polysubstituted by fluorine, preferably trifluoromethyl, (C6-C10)-aryl and (C6-C10)-aryl-(C1-C6)-alkyl;
a 2-, 3-, 4-, 5- or 6-pyridinyl-(C1-C6)-alkyl radical, where the (C1-C6)-alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of (C1-C6)alkyl, halogen or oxo (═O), and the 2-, 3-, 4-, 5- or 6-pyridinyl radical can be unsubstituted or mono- to tetrasubstituted by the same or different substituents from the group of hydrogen, (C1-C6)-alkyl, halogen, nitro, amino, mono-(C1-C6)-alkylamino, di-(C1-C6) alkylamino, hydroxyl, (C1-C6)-alkoxy, benzyloxy, carboxyl, (C1-C6)-alkoxycarbonyl, (C1-C6)-alkoxycarbonylamino or (C1-C6)-alkyl which is mono- or polysubstituted by fluorine, preferably trifluoromethyl, (C6-C10)-aryl and (C6-C10)-aryl-(C1-C6)-alkyl;
a 2-, 3-, 4- or 5-thienyl radical, or a 2-, 3-, 4- or 5-thienyl-(C1-C6) alkyl radical, where the (C1-C6)-alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of (C1-C6)-alkyl, halogen or oxo (═O), and the 2-, 3-, 4- or 5-thienyl radical can be unsubstituted or mono- to trisubstituted by the same or different substituents from the group of hydrogen, (C1-C6)-alkyl, halogen, nitro, amino, mono-(C1-C6)-alkylamino, di-(C1-C6)-alkylamino, hydroxyl, (C1-C6)-alkoxy, benzyloxy, carboxyl, (C1-C6)-alkoxycarbonyl, (C1-C6)-alkoxycarbonylamino or (C1-C6)-alkyl which is mono- or polysubstituted by fluorine, preferably trifluoromethyl, (C6-C10)-aryl and (C6-C10)-aryl-(C1-C6)-alkyl;
a 2-, 4-, or 5-thiazolyl radical, or a 2-, 4-, or 5-thiazolyl-(C1-C6)-alkyl radical, where the (C1-C6)-alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of (C1-C6)-alkyl, halogen or oxo (═O), and the 2-, 4-, or 5thiazolyl radical can be unsubstituted or mono- or disubstituted by the same or different substituents from the group of hydrogen, (C1-C6)-alkyl, halogen, nitro, amino, mono-(C1-C6)-alkylamino, di-(C1-C6)-alkylamino, hydroxyl, (C1-C6)-alkoxy, benzyloxy, carboxyl, (C1-C6)-alkoxycarbonyl, (C1-C6)-alkoxycarbonylamino or (C1-C6)-alkyl which is mono- or polysubstituted by fluorine, preferably trifluoromethyl, (C6-C10)-aryl and (C6-C10)-aryl-(C1-C6)-alkyl;
a 3-, 4-, or 5-isothiazolyl radical, or a 3-, 4-, or 5-isothiazolyl-(C1-C6)-alkyl radical, where the (C1-C6)-alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of (C1-C6)-alkyl, halogen or oxo (═O), and the 3-, 4-, or 5-isothiazolyl radical can be unsubstituted or mono- or disubstituted by the same or different substituents from the group of hydrogen, (C1-C6)-alkyl, halogen, nitro, amino, mono-(C1-C6)-alkylamino, di-(C1-C6)-alkylamino, hydroxyl, (C1-C6)-alkoxy, benzyloxy, carboxyl, (C1-C6)-alkoxycarbonyl, (C1-C6)-alkoxycarbonylamino or (C1-C6)-alkyl which is mono- or polysubstituted by fluorine, preferably trifluoromethyl, (C6-C10)-aryl and (C6-C10)-aryl-(C1-C6)-alkyl;
a 2-, 4-, 5-, 6-, or 7-benzothiazolyl radical, or a 2-, 4-, 5-, 6-, or 7 benzothiazolyl-(C1-C6)-alkyl radical, where the (C1-C6)-alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of (C1-C6)-alkyl, halogen or oxo (═O), and the 2-, 4-, 5-, 6-, or 7-benzothiazolyl radical can be unsubstituted or mono- to tetrasubstituted by the same or different substituents from the group of hydrogen, (C1-C6)-alkyl, halogen, nitro, amino, mono-(C1-C6)-alkylamino, di-(C1-C6)-alkylamino, hydroxyl, (C1-C6)-alkoxy, benzyloxy, carboxyl, (C1-C6)-alkoxycarbonyl, (C1-C6)-alkoxycarbonylamino or (C1-C6)-alkyl which is mono- or poly- substituted by fluorine, preferably trifluoromethyl, (C6-C10)-aryl-and (C6-C10)-aryl-(C1-C6)-alkyl;
a 1-, 2-, 4-, or 5-imidazolyl radical, or a 1-, 2-, 4-, or 5-imidazolyl(C1-C6)-alkyl radical, where the (C1-C6)-alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of (C1-C6)-alkyl, halogen or oxo (═O), and the 1-, 2-, 4-, or 5-imidazolyl radical can be unsubstituted or mono- to trisubstituted by the same or different substituents from the group of hydrogen, (C1-C6)-alkyl, halogen, nitro, amino, mono-(C1-C6)-alkylamino, di-(C1-C6)-alkylamino, hydroxyl, (C1-C6)-alkoxy, benzyloxy, carboxyl, (C1-C6)-alkoxycarbonyl, (C1-C6)-alkoxycarbonylamino or (C1-C6)-alkyl which is mono- or polysubstituted by fluorine, preferably trifluoromethyl, (C6-C10)-aryl and (C6-C10)-aryl-(C1-C6)-alkyl;
a 1-, 3-, 4-, or 5-pyrazolyl radical, or a 1-, 3-, 4- or 5-pyrazolyl-(C1-C6)-alkyl radical, where the (C1-C6)-alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of (C1-C6)-alkyl, halogen or oxo (═O), and the 1-, 3-, 4- or 5-pyrazolyl radical can be unsubstituted or mono- to trisubstituted by the same or different substituents from the group of hydrogen, (C1-C6)-alkyl, halogen, nitro, amino, mono-(C1-C6)-alkylamino, di-(C1-C6)-alkylamino, hydroxyl, (C1-C6)-alkoxy, benzyloxy, carboxyl, (C1-C6)-alkoxycarbonyl, (C1-C6)-alkoxycarbonylamino or (C1-C6)-alkyl which is mono- or polysubstituted by fluorine, preferably trifluoromethyl, (C6-C10)-aryl and (C6-C10)-aryl-(C1-C6)-alkyl;
a 1-, 2-, 3-, 4-, or 5-pyrrolyl radical, or a 1-, 2-, 3-, 4-, or 5-pyrrolyl(C1-C6)-alkyl radical, where the (C1-C6)-alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of (C1-C6)-alkyl, halogen or oxo (═O), and the 1-, 2-, 3-, 4- or 5-pyrrolyl radical can be unsubstituted or mono- to tetrasubstituted by the same or different substituents from the group of hydrogen, (C1-C6)-alkyl, halogen, nitro, amino, mono(C1-C6)-alkylamino, di-(C1-C6)-alkylamino, hydroxyl, (C1-C6)-alkoxy, benzyloxy, carboxyl, (C1-C6)-alkoxycarbonyl, (C1-C6)alkoxycarbonylamino or (C1-C6)-alkyl which is mono- or polysubstituted by fluorine, preferably trifluoromethyl, (C6-C10)-aryl and (C6-C10)-aryl-(C1-C6)-alkyl;
a 1-, 3-, or 5-[1.2.4]-triazolyl radical, or a 1-, 3-, or 5-[1.2.4]-triazolyl-(C1-C6)-alkyl radical, where the (C1-C6)-alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of hydrogen, (C1-C6)-alkyl, halogen or oxo (═O), and the 1-, 3-, or 5-[1.2.4]-triazolyl radical can be unsubstituted or mono- or disubstituted by the same or different substituents from the group of (C1-C6)-alkyl, halogen, nitro, amino, mono-(C1-C6)-alkylamino, di-(C1-C6)-alkylamino, hydroxyl, (C1-C6)-alkoxy, benzyloxy, carboxyl, (C1-C6)-alkoxycarbonyl, (C1-C6)alkoxycarbonylamino or (C1-C6)-alkyl which is mono- or polysubstituted by fluorine, preferably trifluoromethyl, (C6-C10)-aryl and (C6-C10)-aryl-(C1-C6)-alkyl;
a 1-, 4-, or 5-[1.2.3]-triazolyl radical, or a 1-, 4-, or 5-[1.2.3]triazolyl-(C1-C6)-alkyl radical, where the (C1-C6)-alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of (C1-C6)-alkyl, halogen or oxo (═O), and the 1-, 4-, or 5-[1.2.3]-triazolyl radical can be unsubstituted or mono- or disubstituted by the same or different substituents from the group of hydrogen, (C1-C6)-alkyl, halogen, nitro, amino, mono-(C1-C6)-alkylamino, di-(C1-C6)-alkylamino, hydroxyl, (C1-C6)-alkoxy, benzyloxy, carboxyl, (C1-C6)-alkoxycarbonyl, (C1-C6)alkoxycarbonylamino or (C1-C6)-alkyl which is mono- or polysubstituted by fluorine, preferably trifluoromethyl, (C6-C10)-aryl and (C6-C10)-aryl-(C1-C6)-alkyl;
a 1- or 5-[1H]-tetrazolyl radical, or a 1-, or 5-[1H]-tetrazolyl-(C1-C6)-alkyl radical, where the (C1-C6)-alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of (C1-C6)-alkyl, halogen or oxo (═O), and the 1-, or 5-[1H]-tetrazolyl radical can be unsubstituted or substituted by hydrogen, (C1-C6)-alkyl, halogen, nitro, amino, mono-(C1-C6)-alkylamino, di-(C1-C6)-alkylamino, hydroxyl, (C1-C6)alkoxy, benzyloxy, carboxyl, (C1-C6)-alkoxycarbonyl, (C1-C6)-alkoxycarbonylamino or (C1-C6)-alkyl which is mono- or polysubstituted by fluorine, preferably trifluoromethyl, (C6-C10)-aryl and (C6-C10)-aryl-(C1-C6)-alkyl;
a 2- or 5-[2H]-tetrazoyl radical, or a 2- or 5-[2H]-tetrazolyl-(C1-C6) alkyl radical, where the (C1-C6)-alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of (C1-C6)-alkyl, halogen or oxo (═O), and the 2- or 5[2H]-tetrazolyl radical can be unsubstituted or substituted by hydrogen, (C1-C6)-alkyl, halogen, nitro, amino, mono-(C1-C6)alkylamino, di-(C1-C6)-alkylamino, hydroxyl, (C1-C6)-alkoxy, benzyloxy, carboxyl, (C1-C6)-alkoxycarbonyl, (C1-C6)alkoxycarbonylamino or (C1-C6)-alkyl which is mono- or polysubstituted by fluorine, preferably trifluoromethyl, (C6-C10)-aryl and (C6-C10)-aryl-(C1-C6)-alkyl;
a 2-, 4-, or 6-[1.3.5]-triazinyl radical, or a 2-, 4-, or 6-[1.3.5]triazinyl-(C1-C6)-alkyl radical, where the (C1-C6)-alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of hydrogen, (C1-C6)-alkyl, halogen or oxo (═O), and the 2-, 4-, or 6-[1.3.5]-triazinyl radical can be unsubstituted or mono- or disubstituted by the same or different substituents from the group of hydrogen, (C1-C6)-alkyl, halogen, nitro, amino, mono-(C1-C6)-alkylamino, di-(C1-C6)-alkylamino, hydroxyl, (C1-C6)-alkoxy, benzyloxy, carboxyl, (C1-C6)-alkoxycarbonyl, (C1-C6)-alkoxycarbonylamino or (C1-C6)-alkyl which is mono- or polysubstituted by fluorine, preferably trifluoromethyl, (C6-C10)-aryl and (C6-C10)-aryl-(C1-C6)-alkyl;
a 2-, 4-, or 5-oxazolyl radical, or a 2-, 4-, or 5-oxazolyl-(C1-C6)-alkyl radical, where the (C1-C6)-alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of (C1-C6)-alkyl, halogen or oxo (═O), and the 2-, 4-, or 5-oxazolyl radical can be unsubstituted or mono- or disubstituted by the same or different substituents from the group of hydrogen, (C1-C6)-alkyl, halogen, nitro, amino, mono-(C1-C6)-alkylamino, di-(C1-C6)-alkylamino, hydroxyl, (C1-C6)-alkoxy, benzyloxy, carboxyl, (C1-C6)-alkoxycarbonyl, (C1-C6)-alkoxycarbonylamino or (C1-C6)-alkyl which is mono- or polysubstituted by fluorine, preferably trifluoromethyl, (C6-C1-aryl and (C6-C10)-aryl-(C1-C6)-alkyl;
a 3-, 4-, or 5-isoxazolyl radical, or a 3-, 4-, or 5-isoxazolyl-(C1-C6)alkyl radical, where the (C1-C6)-alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of (C1-C6)-alkyl, halogen or oxo (═O), and the 3-, 4-, or 5-isoxazolyl radical can be unsubstituted or mono- or disubstituted by the same or different substituents from the group of hydrogen, (C1-C6)-alkyl, halogen, nitro, amino, mono-(C1-C6)-alkylamino, di(C1-C6)-alkylamino, hydroxyl, (C1-C6)-alkoxy, benzyloxy, carboxyl, (C1-C6)-alkoxycarbonyl, (C1-C6)-alkoxycarbonylamino or (C1-C6)-alkyl which is mono- or polysubstituted by fluorine, preferably trifluoromethyl, (C6-C10)-aryl and (C6-C10)-aryl-(C1-C6)-alkyl;
a 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl radical, or a 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl-(C1-C6)-alkyl radical, where the (C1-C6)-alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of (C1-C6)-alkyl, halogen or oxo (═O), and the 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl radical can be unsubstituted or mono- to hexasubstituted by the same or different substituents from the group of hydrogen, (C1-C6)-alkyl, halogen, nitro, amino, mono-(C1-C6)-alkylamino, di-(C1-C6)-alkylamino, hydroxyl, (C1-C6)-alkoxy, benzyloxy, carboxyl, (C1-C6) alkoxycarbonyl, (C1-C6)-alkoxycarbonylamino or (C1-C6)-alkyl which is mono- or polysubstituted by fluorine, preferably trifluoromethyl, (C6-C10)-aryl and (C6-C10)-aryl-(C1-C6)-alkyl and the isomers, in particular tautomers, diastereomers and enantiomers, and the pharmaceutically acceptable salts, in particular acid addition salts, thereof.
According to a further embodiment, quinoline derivatives of the formula (1) are provided which are characterized in that R, R, R2, R3, X, Z, P, Q, n and m have the meanings given above and R4 represents phenyl which is unsubstituted or substituted by one to five the same or different (C1-C6)-alkoxy groups, where adjacent oxygen atoms may also be linked by (C1-C2)-alkylene groups. According to a further embodiment, quinoline derivatives of the formula (1) are provided which are characterized in that R, R, R2, R3, X, Z, P, Q, n and m have the meanings given above and R4 represents 3,5 dimethoxyphenyl.
According to a further embodiment, quinoline derivatives of the formula (1) are provided which are characterized in that R4 has the meanings given above, R, R1, R2, R3 each represent a hydrogen atom, Z represents an oxygen atom and X represents a nitrogen atom, P and Q each represent two hydrogen atoms (i.e. —CH2—), m is zero and n is the integer 2.
According to a further embodiment, quinoline derivatives of the 20 formula (1) are provided which are characterized in that R, R1, R2, R3 each represent a hydrogen atom, Z represents an oxygen atom, X represents a nitrogen atom, P and Q each represent two hydrogen atoms (i.e. —CH2-), m is zero, n represents the integer 2 and R4 represents a 3,5-dimethoxyphenyl radical.
According to a further aspect of the invention, a process for preparing quinoline derivatives of the formula (1) is provided which is characterized in that a quinoline carboxylic acid of the formula (2)
Figure US06936615-20050830-C00004
in which R, R1, R2, R3 have the meanings given above, Z denotes an oxygen or sulfur atom and Y represents a leaving group such as halogen, hydroxyl, (C1-C6)-alkoxy, preferably methoxy or ethoxy, -0-tosyl, -0mesyl or imidazolyl, is reacted with an amine of the formula (3)
Figure US06936615-20050830-C00005
in which R4, X, P, Q, m and n are as defined above, using, if appropriate, diluents and auxiliaries, and the desired quinoline derivatives are formed.
Synthesis Route:
The compounds of the formula 1 can be obtained according to Scheme 1 below:
Figure US06936615-20050830-C00006
The starting materials (2) and (3) are either commercially available or can be prepared by procedures known per se. The starting materials (2) and (3) are useful intermediates for preparing the quinoline derivatives of the formula (1) according to the invention.
The solvents and auxiliaries to be used, if appropriate, and the reaction parameters to be used, such as reaction temperature and reaction time, are known to the person skilled in the art owing to his expert knowledge.
The quinoline derivatives of the formula (1) according to the invention are suitable as medicaments, in particular as antitumor agents, for treating mammals, in particular man, but also domestic animals such as horses, cattle, dogs, cats, hares, sheep, poultry and the like.
According to a further aspect of the invention, a method for controlling tumors in mammals, in particular man, is provided which is characterized in that at least one quinoline derivative of the formula (1) is administered to a mammal in an amount effective for the treatment of the tumor. The therapeutically effective dose of the quinoline derivative according to the invention in question which is to be administered for the treatment depends inter alia on the nature and the stage of the oncosis, the age and the sex of the patient, the type of administration and the duration of the treatment. Administration can take place orally, rectally, buccally (for example sublingually), parenterally (for example subcutaneously, intramuscularly, intradermally or intravenously), topically or transdermally.
According to a further aspect of the invention, medicaments for the treatment of tumors are provided which are characterized in that they comprise, as active ingredient, at least one quinoline derivative according to any of claims 1 to 4 or a pharmaceutically acceptable salt thereof, if appropriate together with customary pharmaceutically acceptable auxiliaries, additives and carriers. These can be solid, semisolid, liquid or aerosol preparations. Suitable solid preparations are, for example, capsules, powders, granules, tablets. Suitable semisolid preparations are, for example, ointments, creams, gels, pastes, suspensions, oil-in-water and water-in-oil emulsions. Suitable liquid preparations are, for example, sterile aqueous preparations for parenteral administration which are isotonic with the blood of the patient.
The invention is to be illustrated in more detail by the example below, without being restricted to the example.
1-(3,5-dimethoxyphenyl)-4-(4-quinolyl-carbonyl)piperazine
2 g (11.5 mmol) of quinoline-4-carboxylic acid were suspended in 80 ml of DMF. With stirring, 1.74 g (17.2 mmol) of N-methylmorpholine and then a solution of 8.95 g (17.2 mmol) of Py-BOP (1-benzotriazolyltripyrrolidinophosphonium hexafluorophosphate) and 2.56 g (11.5 mmol) of 1-(3,5-dimethoxyphenyl)piperazine in 25 ml of DMF were added to this mixture. The mixture was stirred at RT for 12 h, the DMF was distilled off under reduced pressure and the residue was purified on a silica gel column (Kieselgel 60, from Merck AG, Darmstadt) using the mobile phase dichloromethane/methanol/25 percent ammonia (90:10:1 v/v/v).
Yield: 3.4 g (78.3% of theory)
m.p.: 146-148° C.
1. Antiproliferative Action in Various Tumor Cell Lines
In a proliferation test, the antiproliferative activity of the substance D-43411 was examined using established tumor cell lines. In the test used, the cellular dehydrogenation activity is determined, which makes it possible to determine the vitality of the cell and, indirectly, the cell count. The cell lines used are the human cervical carcinoma cell lines KB/HeLa (ATCC/CCL17), the murine lymphocyte leukaemia L1210 (ATCC CCL-219), the human breast adenocarcinoma line MCF7/ATCC HTB22) and the ovary adenocarcinoma line SKOV-3 (ATCC HTB77). These are established cell lines which are very well characterized and were obtained from ATCC and cultured.
The results shown in Tab. 1 demonstrate the highly potent antiproliferative action of D-43411 in the cell lines SKOV-3, L-1210 and HeLa/KB. Owing to the particularly slow growth of the MCF7 line, the effect of D-43411 in the test period of 48 h is only small (18% inhibition at 3.16_g/ml; thus stated as >3.16).
Tab. 1
In-vitro cytotoxicity in tumor cell lines (values determined from 5 substance
concentrations)
XTT-Assay IC50 [μg/ml]
D number Structure MW SKOV-3 L1210 KB/HeLa MCF7
D-43411
Figure US06936615-20050830-C00007
 		429 <0.0003 <0.0003 <0.0003 >3.16

2. Method
XTT Test for Cellular Dehydrogenase Activity
The adherently growing tumor cell lines HeLa/KB, SKOV-3 and MCF7 and the L1210 leukaemia line, which grows in suspension, were cultivated under standard conditions in an incubator with gas inlet at 37° C., 5% CO2 and 95% atmospheric humidity. On Test Day 1, the adherent cells are detached using trypsine/EDTA and pelleted by centrifugation. The cell pellet is then resuspended in RPMI culture medium at the appropriate cell count and transferred to a 96-well microtitre plate. The plates are then cultivated overnight in the incubator with gas inlet. The test substances are made up as stock solutions in DMSO and, on Test Day 2, diluted with culture medium to the desired concentrations. The substances in the culture medium are then added to the cells and incubated in the incubator with gas inlet for 45 h. Cells which have not been treated with test substance serve as control.
For the XTT assay, 1 mg/ml of XTT (sodium 3′-[1-(phenylaminocarbonyl)-3,4-tetrazolium]-bis(4-methoxy-6-nitro)benzenesulfonic acid) is dissolved in RPMI-1640 medium without Phenol Red. Additionally, a 0.383 mg/ml solution of PMS (N-methyldibenzopyrazine methyl sulfate) in phosphate-buffered saline (PBS) is prepared. On Test Day 4, 75 —1/well of the XTT-PMS mixture are pipetted onto the cell plates, which by now have been incubated with the test substances for 45 h. To this end, the XTT solution is mixed with the PMS solution in a ratio of 50:1 (v/v) shortly before use. The cell plates are then incubated in the incubator with gas inlet for a further 3 h, and the optical density (OD490nm) is determined in a photometer.
Using the OD490nm obtained, the inhibition in percent relative to the control is calculated. The antiproliferative activity is estimated using regression analysis.
EXAMPLE I
Tablet containing 50 mg of active compound
Composition:
(1) Active compound  50.0 mg
(2) Lactose  98.0 mg
(3) Maize starch  50.0 mg
(4) Polyvinylpyrrolidone  15.0 mg
(5) Magnesium stearate  2.0 mg
Total: 215.0 mg

Preparation:
(1), (2) and (3) are mixed and granulated with an aqueous solution of (4). The dried granules are admixed with (5). This mixture is tabletted.
EXAMPLE II
Capsule containing 50 mg of active compound
Composition:
(1) Active compound  50.0 mg
(2) Maize starch, dried  58.0 mg
(3) Lactose powder  50.0 mg
(4) Magnesium stearate  2.0 mg
Total: 160.0 mg

Preparation:
(1) is ground with (3). This ground material is added with vigorous mixing to the mixture of (2) and (4). This powder mixture is, on a capsule filling machine, filled into hard gelatine capsules size 3.
TABLE 8
New Chinolyl-Derivatives with antitumoral activity
Code- M/e
Ex. R R1 R2 R3 X Z n m p Q R4 Nr. (M + H)
1 H H H H N O 2 0 H2 H2 24203 378
2 H H H H N O 2 0 H2 H2 24203 378
HCl-
Salz
3 2-(4- H 6-CH3 7-Cl N O 2 0 H2 H2 68780 537
chloro=
phenyl)
4 2-CH3 3-OH H H N O 2 0 H2 H2 68675 408
5 2-(3,4- H H 7-CH3 N O 2 0 H2 H2 68823 528
dimeth=
oxyphenyl)

Claims (14)

1. Quinoline derivatives according to the formula 1
Figure US06936615-20050830-C00008
in which
R, R1, R2, R3 can be attached to any of the quinoline carbon atoms C2 to C8, are identical or different and independently of one another denote hydrogen, straight-chain or branched C1-8 alkyl, C3-7 cycloalkyl, straight-chain or branched C1-8 alkylcarbonyl, straight-chain or branched C1-8 alkoxy, halogen, aryl-C1-8 alkoxy, nitro, amino, mono-C1-4 alkylamino, di-C1-4 alkylamino, C1-8 alkoxycarbonylamino, C1-6 alkoxycarbonylamino-C1-8 alkyl, cyano, straight-chain or branched cyano-(C1-C6)-alkyl, carboxyl, C1-8 alkoxycarbonyl, C1-4 alkyl which is substituted by one or more fluorine atoms, carboxy-C1-8 alkyl or C1-8 alkoxycarbonyl-C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, straight-chain or branched cyano-C1-6 alkyl, aryl, where the aryl radical can be unsubstituted or mono- or polysubstituted by identical or different substituents from the group consisting of halogen, straight-chain or branched C1-8 alkyl, C3-7 cycloalkyl, carboxyl, straight-chain or branched C1-8 alkoxycarbonyl, by trifluoromethyl, hydroxyl, straight-chain or branched C1-8 alkoxy, benzyloxy, nitro, amino, mono-C1-4 alkylamino, di-C1-4 alkylamino, cyano, straight-chain or branched cyano-C1-6 alkyl, where R and R1 or R2 and R3 can form a fused aromatic 6-membered ring with the quinoline ring forming an acridine ring which for its part can be substituted at any C atom ring position by the radicals R, R1, R2 and R3 having the meanings mentioned above;
P and Q are each 2 hydrogen atoms;
Z is oxygen or sulfur, where the radical
Figure US06936615-20050830-C00009
substituted on the quinoline heterocycle can be attached to C atoms C2-8 of the quinoline ring skeleton;
X is nitrogen;
n is 1 or 2 and m is 0 or 1, with the proviso that the sum of n and m is 2;
R4 is a straight-chain or branched C2-20 alkenyl or alkynyl which can be unsaturated or can optionally be substituted at the same or different C atoms by one, two or more aryl, heteroaryl, halogen, cyano, C1-6 alkoxycarbonylamino, C1-6 alkoxy, amino, mono-C1-4 alkylamino or di-C1-4 alkylamino; a straight-chain or branched C1-20 alkyl which can be unsubstituted or can optionally be substituted at the same or different C atoms by two or more aryl, heteroaryl, halogen, cyano, C1-6 alkoxycarbonylamino, C1-6 alkoxy, amino, mono-C1-4 alkylamino or di-C1-4 alkylamino; a straight-chain or branched C1-20 alkyl which can be unsubstituted or can optionally be substituted at the same or different C atoms by one heteroaryl, halogen, cyano, C1-6 alkoxycarbonylamino, C1-6 alkoxy, amino, mono-C1-4 alkylamino or di-C1-4 alkylamino; a C6-14 aryl radical, or a C2-10 heteroaryl or C2-10 heteroaryl-C1-4 alkyl radical which contains one or more heteroatoms selected from the group consisting of N, O and S, where the C1-4 alkyl radical can be unsubstituted or mono- or polysubstituted by identical or different substituents from the group consisting of C1-6 alkyl, halogen or oxo (═O) and where the C6-14 aryl or C2-10 heteroaryl radical can be unsubstituted or mono- or polysubstituted by identical or different substituents from the group consisting of straight-chain or branched C1-8 alkyl, C3-7 cycloalkyl, halogen, cyano, C1-6 alkoxycarbonylamino, C1-6 alkoxy, carboxyl, C1-8 alkoxycarbonyl, or straight-chain or branched C1-6 alkyl which is substituted by one or more fluorine atoms, hydroxyl, straight-chain or branched C1-8 alkoxy, where adjacent oxygen atoms can also be linked by C1-2 alkylene groups, benzyloxy, nitro, amino, mono-C1-4 alkylamino, di-C1-4 alkylamino, or aryl, which can be unsubstituted or mono- or polysubstituted by identical or different substituents from the group consisting of straight-chain or branched C1-8 alkyl, C3-7 cycloalkyl, carboxyl, straight-chain or branched C1-8 alkoxycarbonyl, trifluoromethyl, hydroxyl, straight-chain or branched C1-8 alkoxy, benzyloxy, nitro, amino, mono-C1-4 alkylamino, di-C1-4 alkylamino, cyano, straight-chain or branched cyano-C1-6 alkyl; or C6-14 aryl-C1-4 alkyl radical, where the C1-4 alkyl radical can be unsubstituted or mono- or polysubstituted by identical or different substituents from the group consisting of C1-6 alkyl, halogen or oxo (═O) and where the C6-14 aryl is mono- or polysubstituted by identical or different substituents from the group consisting of straight-chain or branched C1-8 alkyl, C3-7 cycloalkyl, halogen, cyano, C1-6 alkoxycarbonylamino, carboxyl, C1-8 alkoxycarbonyl, or straight-chain or branched C1-6 alkyl which is substituted by one or more fluorine atoms, hydroxyl, straight-chain or branched C1-8 alkoxy, where adjacent oxygen atoms can also be linked by C1-2 alkylene groups, benzyloxy, nitro, amino, mono-C1-4 alkylamino, di-C1-4 alkylamino, or aryl, which can be unsubstituted or mono- or polysubstituted by identical or different substituents from the group consisting of straight-chain or branched C1-8 alkyl, C3-7 cycloalkyl, carboxyl, straight-chain or branched C1-8 alkoxycarbonyl, trifluoromethyl, hydroxyl, straight-chain or branched C1-8 alkoxy, benzyloxy, nitro, amino, mono-C1-4 alkylamino, di-C1-4 alkylamino, cyano, straight-chain or branched cyano-C1-6 alkyl;
and their structural isomers and stereoisomers and their pharmaceutically acceptable salts.
2. A pharmaceutical composition which comprises as active ingredient at least one quinoline derivative according of claim 1, together with pharmaceutically acceptable carrier.
3. The pharmaceutically acceptable acid addition salt of the quinoline derivative of claim 1, when formed with one of the acids hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, acetic acid, tartaric acid, malic acid, maleic acid, embonic acid, malonic acid, trifluoroacetic acid, methanesulfonic acid, and sulfoacetic acid.
4. The quinoline derivative of claim 1, wherein in R, R1, R2 and R3, said C1-8 alkylcarbonyl is acetyl, said C1-8 alkoxy is benzyloxy or phenylethoxy, said C1-4 alkyl which is substituted by one or more fluorine atoms is trifluoromethyl, said C2-6 alkenyl is allyl, said C2-6 alkynyl is ethynyl or propargyl, said cyano-C1-6 alkyl is cyanomethyl, said C1-8 alkoxy-carbonyl is tert-butoxycarbonyl, and said C1-8 alkoxy is methoxy or ethoxy, and in R4 said C1-6 alkyl which is substituted by one or more fluorine atoms is trifluoromethyl, said C1-8 alkoxy is methoxy or ethoxy, and said C1-2 alkylene group is a methylene group.
5. The quinoline derivative of formula 1 of claim 1, wherein R, R1, R2, R3, X, Z, P, Q, n and m have the meanings given in claim 1;
R4 is a straight-chain or branched C2-20 alkenyl or alkynyl radical which can be unsubstituted or optionally substituted on the same or different C atoms by one, two or more aryl, heteroaryl, halogen, C1-6 alkoxy, amino, mono- C1-4 alkylamino or di-C1-4 alkylamino; a straight-chain or branched C1-20 alkyl radical which can be unsubstituted or optionally substituted on the same or different C atoms by two or more aryl, heteroaryl, halogen, C1-6 alkoxy, amino, mono-C1-4 alkylamino or di-C1-4 alkylamino; or a straight-chain or branched C1-20 alkyl radical which can be unsubstituted or optionally substituted on the same or different C atoms by one heteroaryl, halogen, C1-6 alkoxy, amino, mono-C1-4 alkylamino or di-C1-4 alkylamino;
a phenyl ring or a naphthyl ring, each of which can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of straight-chain or branched C1-8 alkyl, C3-7 cycloalkyl, halogen, cyano, C1-6 alkoxycarbonylamino, C1-6 alkoxy, carboxyl, C1-6 alkoxycarbonyl, straight-chain or branched C1-6 alkyl which is substituted by one or more fluorine atoms, hydroxyl, straight-chain or branched C1-6 alkoxy, benzyloxy, nitro, amino, mono-C1-4 alkylamino, di-C1-4 alkylamino, aryl, which can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of straight-chain or branched C1-8 alkyl, C3-7 cycloalkyl, carboxyl, straight-chain or branched C1-8 alkoxycarbonyl, by trifluoromethyl, hydroxyl, straight-chain or branched C1-8 alkoxy, benzyloxy, nitro, amino, mono-C1-4 alkylamino, di-C1-4 alkylamino, cyano, straight-chain or branched cyano-C1-6 alkyl;
a 2-, 4-, 5- or 6-pyrimidinyl radical, or a 2-, 4-, 5- or 6-pyrimidinyl-C1-4 alkyl radical, wherein the C1-4 alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of C1-6 alkyl, halogen or oxo (═O) and the 2-, 4-, 5- or 6-pyrimidinyl radical can be unsubstituted or mono- or up to trisubstituted by the same or different substituents from the group of hydrogen, or Y
wherein Y is a C1-6 alkyl, halogen, nitro, amino, mono-C1-6 alkylamino, di-C1-6 alkylamino, hydroxyl, C1-6 alkoxy, benzyloxy, carboxyl, C1-6 alkoxycarbonyl, C1-6 alkoxycarbonylamino or C1-6 alkyl which is mono- or polysubstituted by fluorine, C6-10 aryl and C6-10 aryl-C1-6 alkyl;
a 3-, 4-, 5- or 6-pyridazinyl radical, or a 3-, 4-, 5- or 6pyridazinyl-C1-4 alkyl radical, wherein the C1-4 alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of C1-6 alkyl, halogen or oxo (═O), and the 3-, 4-, 5- or 6-pyridazinyl radical can be unsubstituted or mono- or up to trisubstituted by the same or different substituents from the group of hydrogen, or Y;
a 2-, 3-, 5- or 6-pyrazinyl radical, or a 2-, 3-, 5- or 6-pyrazinyl-C1-4 alkyl radical, wherein the C1-4 alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of C1-6 alkyl, halogen or oxo (═O), and the 2-, 3-, 5- or 6-pyrazinyl radical can be unsubstituted or mono- or up to trisubstituted by the same or different substituents from the group of hydrogen, or Y;
a 3-, 4-, 5-, 6-, 7-, or 8-cinnolinyl radical, or a 3-, 4-, 5-, 6-, 7-, or 8-cinnolinyl-C1-4 alkyl radical, wherein the C1-4 alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of C1-4 alkyl, halogen or oxo (═O), and the 3-, 4-, 5-, 6-, 7-, or 8-cinnolinyl radical can be unsubstituted or mono- or up to pentasubstituted by the same or different substituents from the group of hydrogen, or Y;
a 2-, 4-, 5-, 6-, 7-, or 8-quinazolinyl radical, or a 2-, 4-, 5-, 6-, 7 or 8-quinazolinyl-C1-4 alkyl radical, wherein the C1-4 alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group or hydrogen, C1-6 alkyl, halogen or oxo (═O), and the 2-, 4-, 5-, 6-, 7-, or 8-quinazolinyl radical can be unsubstituted or mono- or up to pentasubstituted by the same or different substituents from the group of hydrogen, or Y;
a 2-, 3-, 5-, 6-, 7-, or 8-quinoxalinyl radical, or a 2-, 3-, 5-, 6-, 7-, or 8-quinoxalinyl-C1-4 alkyl radical, wherein the C1-4 alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of C1-6 alkyl, halogen or oxo (═O), and the 2-, 3-, 5-, 6-, 7-, or 8-quinoxalinyl radical can be unsubstituted or mono- or up to pentasubstituted by the same or different substituents from the group of hydrogen, or Y;
a 1-, 4-, 5-, 6-, 7-, or 8-phthalazinyl radical, or a 1-, 4-, 5-, 6-, 7-, or 8-phthalazinyl-C1-4 alkyl radical, wherein the C1-4 alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of C1-6 alkyl, halogen or oxo (═O), and the 1-, 4-, 5-, 6-, 7-, or 8-phthalazinyl radical can be unsubstituted or mono- or up to pentasubstituted by the same or different substituents from the group of hydrogen, or Y;
a 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl radical, or a 2-, 3-, 4-, 5-, 6-, 7 or 8-quinolyl-C1-4 alkyl radical, wherein the C1-4 alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of C1-6 alkyl, halogen or oxo (═O), and the 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl radical can be unsubstituted or mono- or up to hexasubstituted by the same or different substituents from the group of hydrogen, or Y;
a 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl radical, or a 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl-C1-4 alkyl radical, wherein the C1-4 alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of C1-6 alkyl, halogen or oxo (═O), and the 1-, 4-, 5-, 6-, 7- or 8-isoquinolyl radical can be unsubstituted or mono- or up to hexasubstituted by the same or different substituents from the group of hydrogen, or Y;
a 2-, 6-, 8- or 9-[9H]-purinyl radical, or a 2-, 6-, 8- or 9-[9H]-purinyl-C1-4 alkyl radical, wherein the C1-4 alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of C1-6 alkyl, halogen or oxo (═O), and the 2-, 6-, 8- or 9-[9H]-purinyl radical can be unsubstituted or mono- to trisubstituted by the same or different substituents from the group of hydrogen, or Y;
a 2-, 6-, 7- or 8-[7H]-purinyl radical, or a 2-, 6-, 7- or 8-[7H]-purinyl-C1-4 alkyl radical, wherein the C1-4 alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of C1-6 alkyl, halogen or oxo (═O), and the 2-, 6-, 7- or 8-[7H]-purinyl radical can be unsubstituted or mono- or up to trisubstituted by the same or different substituents from the group of hydrogen, or Y;
a 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl radical, or a 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl-C1-4 alkyl radical, where the C1-6 alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of C1-6 alkyl, halogen or oxo (═O), and the 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl radical can be unsubstituted or mono- to octasubstituted by the same or different substituents from the group of hydrogen, or Y;
a 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-phenanthridinyl radical, or a 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9- phenanthridinyl-C1-6 alkyl radical, wherein the C1-6 alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of hydrogen, C1-6 alkyl, halogen or oxo (═O), and the 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-phenanthridinyl radical can be unsubstituted or mono- or up to octasubstituted by the same or different substituents of Y;
a 2-, 3-, 4-, 5- or 6-pyridyl radical where the 2-, 3-, 4-, 5- or 6pyridyl radical an be unsubstituted or mono- or up to tetrasubstituted by the same or different substituents from the group of hydrogen, or Y;
a 2-, 3-, 4-, 5- or 6-pyridinyl-C1-6 alkyl radical, wherein the C1-6 alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of C1-6 alkyl, halogen or oxo (═O), and the 2-, 3-, 4-, 5- or 6-pyridinyl radical can be unsubstituted or mono- or up to tetrasubstituted by the same or different substituents from the group of hydrogen, or Y;
a 2-, 3-, 4- or 5-thienyl radical, or a 2-, 3-, 4- or 5-thienyl-C1-6 alkyl radical wherein the C1-6 alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of C1-6 alkyl, halogen or oxo (═O), and the 2-, 3-, 4- or 5-thienyl radical can be unsubstituted or mono- or up to trisubstituted by the same or different substituents from the group of hydrogen, or Y;
a 2-, 4-, or 5-thiazolyl radical, or a 2-, 4-, or 5-thiazolyl C1-6 alkyl C1-6 alkyl radical, wherein the C1-6 alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of C1-6 alkyl, halogen or oxo (═O), and the 2-, 4-, or 5-thiazolyl radical can be unsubstituted or mono- or disubstituted by the same or different substituents from the group of hydrogen, or Y;
a 3-, 4-, or 5-isothiazolyl radical, or a 3-, 4-, or 5-isothiazolyl-C1-6 alkyl radical, wherein the C1-6 alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of C1-6 alkyl, halogen or oxo (═O), and the 3-, 4-, or 5-isothiazolyl radical can be unsubstituted or mono- or disubstituted by the same or different substituents from the group of hydrogen, or Y;
a 2-, 4-, 5-, 6-, or 7-benzothiazolyl radical, or a 2-, 4-, 5-, 6-, or 7-benzothiazolyl-C1-6 alkyl radical, wherein the C1-6 alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of C1-6 alkyl, halogen or oxo (═O),and the 2-, 4-, 5-, 6-, or 7-benzothiazolyl radical can be unsubstituted or mono- or up to tetrasubstituted by the same or different substituents from the group of hydrogen, or Y;
a 1-, 2-, 4-, or 5-imidazolyl radical, or a 1-, 2-, 4-, or 5 imidazolyl-C1-6 alkyl radical, wherein the C1-6 alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of C1-6 alkyl, halogen or oxo (═O), and the 1-, 2-, 4-, or 5-imidazolyl radical can be unsubstituted or mono- or up to trisubstituted by the same or different substituents from the group of hydrogen, or Y;
a 1-, 3-, 4-, or 5-pyrazolyl radical, or a 1-, 3-, 4- or 5-pyrazolyl-C1-6 alkyl radical, wherein the C1-6 alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of C1-6 alkyl, halogen or oxo (═O), and the 1-, 3- , 4- or 5-pyrazolyl radical can be unsubstituted or mono- or up to trisubstituted by the same of different substituents from the group of hydrogen, or Y;
a 1-, 2-, 3-, 4-, or 5-pyrrolyl radical, or a 1-, 2-, 3-, 4-, or 5-pyrrolyl-C1-6 alkyl radical, wherein the C1-6 alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of C1-6 alkyl, halogen or oxo (═O), and the 1-, 2-, 3-, 4- or 5-pyrrolyl radical can be unsubstituted or mono- or up to tetrasubstituted by the same or different substituents from the group of hydrogen, or Y;
a 1-, 3-, or 5-[1.2.4]-triazolyl radical, or a 1-, 3-, or 5-[1.2.4]-triazolyl-C1-6 alkyl radical, wherein the C1-6 alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of hydrogen, C1-6 alkyl, halogen or oxo (═O), and the 1-, 3-, or 5-[1.2.4]-triazolyl radical can be unsubstituted or mono- or disubstituted by the same or different substituents from Y;
a 1-, 4-, or 5-[1.2.3]-triazolyl radical, or a 1-, 4-, or 5-[1.2.3]-triazolyl-C1-6 alkyl radical, wherein the C1-6 alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of C1-6 alkyl, halogen or oxo (═O), and the 1-, 4-, or 5-[1.2.3]-triazolyl radical can be unsubstituted or mono- or disubstituted by the same or different substituents from the group of hydrogen, or Y;
a 1- or 5-[1H]-tetrazolyl radical, or a 1-, or 5-[1H]-tetrazolyl-C1-6 alkyl radical, wherein the C1-6 alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of C1-6 alkyl, halogen or oxo (═O), and the 1-, or 5-[1H]-tetrazolyl radical can be unsubstituted or substituted by hydrogen, or Y;
a 2- or 5-[2H]-tetrazoyl radical, or a 2- or 5-[2H]-tetrazolyl-C1-6 alkyl radical, wherein the C1-6 alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of C1-6 alkyl, halogen or oxo (═O), and the 2- or 5-[2H]-tetrazolyl radical can be unsubstituted or substituted by hydrogen, or Y;
a 2-, 4-, or 6-[1.3.5]-triazinyl radical, or a 2-, 4-, or 6-[1.3.5]-triazinyl-C1-6 alkyl radical, wherein the C1-6 alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of hydrogen, C1-6 alkyl, halogen or oxo (═O), and the 2-, 4-, or 6-[1.3.5]-triazinyl radical can be unsubstituted or mono- or disubstituted by the same or different substituents from the group of hydrogen, or Y;
a 2-, 4-, or 5-oxazolyl radical, or a 2-, 4-, or 5-oxazolyl-C1-6 alkyl radical, wherein the C1-6 alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of C1-6 alkyl, halogen or oxo (═O), and the 2-, 4-, or 5-oxazolyl radical can be unsubstituted or mono- or disubstituted by the same or different substituents from the group of hydrogen, or Y;
a 3-, 4-, or 5-isoxazolyl radical, or a 3-, 4-, or 5-isoxazolyl-C1-6 alkyl radical, wherein the C1-6 alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of C1-6 alkyl, halogen or oxo (═O), and the 3-, 4- , or 5-isoxazolyl radical can be unsubstituted or mono- or disubstituted by the same or different substituents from the group of hydrogen, or Y;
a 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl radical, or a 1-, 2-, 3-, 4-, 5-, 6 or 7-indolyl C1-6 alkyl radical, wherein the C1-6 alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of C1-6 alkyl, halogen or oxo (═O), and the 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl radical can be unsubstituted or mono- or up to hexasubstituted by the same or different substituents from the group of hydrogen, or Y.
6. The quinoline derivative of claim 1, wherein in R4 said C1-6 alkyl which is substituted by one or more fluorine atoms is trifluoromethyl, and said C1-8 alkoxy is methoxy or ethoxy.
7. The quinoline derivative of claim 1, wherein R, R1, R2, R3, X, Z, P, Q, n and m have the meanings given above, and R4 is phenyl which is unsubstituted or substituted by one to five the same or different C1-6 alkoxy groups, where adjacent oxygen atoms can also be linked by C1-2 alkylene groups.
8. The quinoline derivative of claim 1, wherein R, R1, R2, R3, X, Z, P, Q, n and m have the meanings given above and R4 is 3,5-dimethoxyphenyl.
9. The quinoline derivative of claim 1, wherein R4 has the meanings given above, R, R1, R2, R3 each is hydrogen, Z is an oxygen atom, X is a nitrogen atom, P and Q are each two hydrogen atoms as in —CH2—, m is zero, and n is 2.
10. The quinoline derivative of claim 1, wherein R, R1, R2, R3 are each a hydrogen atom, Z is an oxygen atom, X is a nitrogen atom, P and Q each are two hydrogen atoms as in —CH2—, m is zero, n is 2, and R4 is a 3,5-dimethoxyphenyl radical.
11. A method for treating a cancer in a mammal, which comprises administering to a mammal in need thereof an effective amount of a quinoline derivative according to the formula 1
Figure US06936615-20050830-C00010
in which
R, R1, R2, R3 can be attached to any of the quinoline carbon atoms C2 to C8, are identical or different and independently of one another denote hydrogen, straight-chain or branched C1-8 alkyl, C3-7 cycloalkyl, straight-chain or branched C1-8 alkylcarbonyl, straight-chain or branched C1-8 alkoxy, halogen, aryl-C1-8 alkoxy, nitro, amino, mono-C1-4 alkylamino, di-C1-4 alkylamino, C1-8 alkoxycarbonylamino, C1-6 alkoxycarbonylamino-C1-8 alkyl cyano, straight-chain or branched cyano-(C1-C6)-alkyl, carboxyl, C1-8 alkoxycarbonyl, C1-4 alkyl which is substituted by one or more fluorine atoms, carboxy-C1-8 alkyl or C1-8 alkoxycarbonyl-C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, straight-chain or branched cyano-C1-6 alkyl, aryl, where the aryl radical can be unsubstituted or mono- or polysubstituted by identical or different substituents from the group consisting of halogen, straight-chain or branched C1-8 alkyl, C3-7 cycloalkyl, carboxyl, straight-chain or branched C1-8 alkoxycarbonyl, by trifluoromethyl, hydroxyl, straight-chain or branched C1-8 alkoxy, benzyloxy, nitro, amino, mono-C1-4 alkylamino, di-C1-4 alkylamino, cyano, straight-chain or branched cyano-C1-6 alkyl, where R and R1 or R2 and R3 can form a fused aromatic 6-membered ring with the quinoline ring forming an acridine ring which for its part can be substituted at any C atom ring position by the radicals R, R1, R2 and R3 having the meanings mentioned above;
P and Q are each 2 hydrogen atoms;
Z is oxygen or sulfur, where the radical
Figure US06936615-20050830-C00011
substituted on the quinoline heterocycle can be attached to C atoms C2-8 of the quinoline ring skeleton;
X is nitrogen;
n is 1 or 2 and m is 0 or 1, with the proviso that the sum of n and m is 2;
R4 is a straight-chain or branched C1-20 alkyl, C2-20 alkenyl or C2-20 alkynyl radical which can be unsubstituted or can optionally be substituted at the same or different C atoms by one, two or more aryl, heteroaryl, halogen, cyano, C1-6 alkoxycarbonylamino, C1-6 alkoxy, amino, mono-C1-4 alkylamino or di-C1-4 alkylamino; a C6-14 aryl radical, C6-14 aryl-C1-4 alkyl radical, or a C2-10 heteroaryl or C2-10 heteroaryl-C1-4 alkyl radical which contains one or more heteroatoms selected from the group consisting of N, O and S, where the C1-4 alkyl radical can be unsubstituted or mono- or polysubstituted by identical or different substituents from the group consisting of C1-6 alkyl, halogen or oxo (═O) and where the C6-14 aryl or C2-10 heteroaryl radical can be unsubstituted or mono- or polysubstituted by identical or different substituents from the group consisting of straight-chain or branched C1-8 alkyl, C3-7 cycloalkyl, halogen, cyano, C1-6 alkoxycarbonylamino, C1-6 alkoxy, carboxyl, C1-8 alkoxycarbonyl, or straight-chain or branched C1-6 alkyl which is substituted by one or more fluorine atoms, hydroxyl, straight-chain or branched C1-8 alkoxy, where adjacent oxygen atoms can also be linked by C1-2 alkylene groups, benzyloxy, nitro, amino, mono-C1-4 alkylamino, di-C1-4 alkylamino, or aryl, which can be unsubstituted or mono- or polysubstituted by identical or different substituents from the group consisting of straight-chain or branched C1-8 alkyl, C3-7 cycloalkyl, carboxyl, straight-chain or branched C1-8 alkoxycarbonyl, trifluoromethyl, hydroxyl, straight-chain or branched C1-8 alkoxy, benzyloxy, nitro, amino, mono-C1-4 alkylamino, di-C1-4 alkylamino, cyano, straight-chain or branched cyano-C1-6 alkyl;
and their structural isomers and stereoisomers and their pharmaceutically acceptable salts;
wherein said cancer is selected from the group consisting of cervical carcinoma, lymphocyte leukemia, breast adenocarcinoma, ovarian adenocarcinoma, and pulmonary carcinoma.
12. The method of claim 11, wherein R4 is a straight-chain or branched C2-20 alkenyl or alkynyl which can be unsubstituted or can optionally be substituted at the same or different C atoms by one, two or more aryl, heteroaryl, halogen, cyano, C1-6 alkoxycarbonylamino, C1-6 alkoxy, amino, mono-C1-4 alkylamino or di-C1-4 alkylamino; a straight-chain or branched C1-20 alkyl which can be unsubstituted or can optionally be substituted at the same or different C atoms by two or more aryl heteroaryl, halogen, cyano, C1-6 alkoxycarbonylamino, C1-6 alkoxy, amino, mono-C1-4 alkylamino or di-C1-4 alkylamino; a straight-chain or branched C1-20 alkyl which can be unsubstituted or can optionally be substituted at the same or different C atoms by one heteroaryl, halogen, cyano, C1-6 alkoxycarbonylamino, C1-6 alkoxy, amino, mono-C1-4 alkylamino or di-C1-4 alkylamino; a straight-chain or branched C1-20 alkyl which can be unsubstituted or can optionally be substituted at the same or different C atoms by one heteroaryl, halogen, cyano, C1-6 alkoxycarbonylamino, C1-6 alkoxy, amino, mono-C1-4 alkylamino or di-C1-4 alkylamino; a C6-14 aryl radical, or a C2-10 heteroaryl or C2- 10 heteroaryl-C1-4 alkyl radical which contains one or more heteroatoms selected from the group consisting of N, O and S, where the C1-4 alkyl radical can be unsubstituted or mono- or polysubstituted by identical or different substituents from the group consisting of C1-6 alkyl, halogen or oxo (═O) and where the C6-14 aryl or C2-10 heteroaryl radical can be unsubstituted or mono- or polysubstituted by identical or different substituents from the group consisting of straight-chain or branched C1-8 alkyl, C3-7 cycloalkyl, halogen, cyano, C1-6 alkoxycarbonylamino, C1-6 alkoxy, carboxyl, C1-8 alkoxycarbonyl, or straight-chain or branched C1-6 alkyl which is substituted by one or more fluorine atoms, hydroxyl, straight-chain or branched C1-8 alkoxy, where adjacent oxygen atoms can also be linked by C1-2 alkylene groups, benzyloxy, nitro, amino, mono-C1-4 alkylamino, di-C1-4 alkylamino, or aryl, which can be unsubstituted or mono- or polysubstituted by identical or different substituents from the group consisting of straight-chain or branched C1-8 alkyl, C3-7 cycloalkyl, carboxyl, straight-chain or branched C1-8 alkoxycarbonyl, trifluoromethyl, hydroxyl, straight-chain or branched C1-8 alkoxy, benzyloxy, nitro, amino, mono-C1-4 alkylamino, di-C1-4 alkylamino, cyano, straight-chain or branched cyano-C1-6 alkyl; or C6-14 aryl-C1-4 alkyl radical, where the C1-4 alkyl radical can be unsubstituted or mono- or polysubstituted by identical or different substituents from the group consisting of C1-6 alkyl, halogen or oxo (═O) and where the C6-14 aryl is mono- or polysubstituted by identical or different substituents from the group consisting of straight-chain or branched C1-8 alkyl, C3-7 cycloalkyl, halogen, cyano, C1-6 alkoxycarbonylamino, carboxyl, C1-8 alkoxycarbonyl, or straight-chain or branched C1-6 alkyl which is substituted by one or more fluorine atoms, hydroxyl, straight-chain or branched C1-8 alkoxy, where adjacent oxygen atoms can also be linked by C1-2 alkylene groups, benzyloxy, nitro, amino, mono-C1-4 alkylamino, di-C1-4 alkylamino, or aryl, which can be unsubstituted or mono- or polysubstituted by identical or different substituents from the group consisting of straight-chain or branched C1-8 alkyl, C3-7 cycloalkyl, carboxyl, straight-chain or branched C1-8 alkoxycarbonyl, trifluoromethyl, hydroxyl, straight-chain or branched C1-8 alkoxy, benzyloxy, nitro, amino, mono-C1-4 alkylamino, di-C1-4 alkylamino, cyano, straight-chain or branched cyano-C1-6 alkyl.
13. A method for inhibiting the growth of tumor cells in mammal, comprising administering to a mammal in need thereof a tumor inhibiting amount of a quinoline derivative according to the formula 1
Figure US06936615-20050830-C00012
in which
R, R1, R2, R3 can be attached to any of the quinoline carbon atoms C2 to C8, are identical or different and independently of one another denote hydrogen, straight-chain or branched C1-8 alkyl, C3-7 cycloalkyl, straight-chain or branched C1-8 alkylcarbonyl, straight-chain or branched C1-8 alkoxy, halogen, aryl-C1-8 alkoxy, nitro, amino, mono-C1-4 alkylamino, di-C1-4 alkylamino, C1-8 alkoxycarbonylamino, C1-6 alkoxycarbonylamino-C1-8 alkyl, cyano, straight-chain or branched cyano-(C1-C6)-alkyl, carboxyl, C1-8 alkoxycarbonyl, C1-4 alkyl which is substituted by one or more fluorine atoms, carboxy-C1-8 alkyl or C1-8 alkoxycarbonyl-C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, straight-chain or branched cyano-C1-6 alkyl, aryl, where the aryl radical can be unsubstituted or mono- or polysubstituted by identical or different substituents from the group consisting of halogen, straight-chain or branch C1-8 alkyl, C3-7 cycloalkyl, carboxyl, straight-chain or branched C1-8 alkoxycarbonyl, by trifluoromethyl, hydroxyl, straight-chain or branched C1-8 alkoxy, benzyloxy, nitro, amino, mono-C1-4 alkylamino, di-C1-4 alkylamino, cyano, straight-chain or branched cyano-C1-6 alkyl, where R and R1 or R2 and R3 can form a fused aromatic 6-membered ring with the quinoline ring forming an acridine ring which or its part can be substituted at any C atom ring position by the radicals R, R1, R2 and R3 having the meanings mentioned above;
P and Q are each 2 hydrogen atoms;
Z is oxygen or sulfur, where the radical
Figure US06936615-20050830-C00013
substituted on the quinoline heterocycle can be attached to C atoms C2-8 of the quinoline ring skeleton;
X is nitrogen;
n is 1 or 2 and m is 0 or 1, with the proviso that the sum of n and m is 2;
R4 is a straight-chain or branched C1-20 alkyl, alkenyl or alkynyl radical which can be unsubstituted or can optionally be substituted at the same or different C atoms by one, two or more aryl, heteroaryl, halogen, cyano, C1-6 alkoxycarbonylamino, C1-6 alkoxy, amino, mono-C1-4 alkylamino or di-C1-4 alkylamino; a C6-14 aryl radical, C6-14 aryl-C1-4 alkyl radical, or a C2-10 heteroaryl or C2-10 heteroaryl-C1-4 alkyl radical which contains one or more heteroatoms selected from the group consisting of N, O and S, where the C1-4 alkyl radical can be unsubstituted or mono- or polysubstituted by identical or different substituents from the group consisting of C1-6 alkyl, halogen or oxo (═O) and where the C6-14 aryl or C2-10 heteroaryl radical can be unsubstituted or mono- or polysubstituted by identical or different substituents from the group consisting of straight-chain or branched C1-8 alkyl, C3-7 cycloalkyl, halogen, cyano, C1-6 alkoxycarbonylamino, C1-6 alkoxy, carboxyl, C1-8 alkoxycarbonyl, or straight-chain or branched C1-6 alkyl which is substituted by one or more fluorine atoms, hydroxyl, straight-chain or branched C1-8 alkoxy, where adjacent oxygen atoms can also be linked by C1-2 alkylene groups, benzyloxy, nitro, amino, mono-C1-4 alkylamino, di-C1-4 alkylamino, or aryl, which can be unsubstituted or mono- or polysubstituted by identical or different substituents from the group consisting of straight-chain or branched C1-8 alkyl, C3-7 cycloalkyl, carboxyl, straight-chain or branched C1-8 alkoxycarbonyl, trifluoromethyl, hydroxyl, straight-chain or branched C1-8 alkoxy, benzyloxy, nitro, amino, mono-C1-4 alkylamino, di-C1-4 alkylamino, cyano, straight-chain or branched cyano-C1-6 alkyl;
and their structural isomers and stereoisomers and their pharmaceutically acceptable salts;
wherein said tumor is selected from the group consisting of cervical carcinoma, lymphocyte leukemia, breast adenocarcinoma, ovarian adenocarcinoma, and pulmonary carcinoma.
14. The method of claim 13, wherein R4 is a straight-chain or branched C2-20 alkenyl or alkynyl which can be unsubstituted or can optionally be substituted at the same or different C atoms by one, two or more aryl, heteroaryl, halogen, cyano, C1-6 alkoxycarbonylamino, C1-6 alkoxy, amino, mono-C1-4 alkylamino or di-C1-4 alkylamino; a straight-chain or branched C1-20 alkyl which can be unsubstituted or can optionally be substituted at the same or different C atoms by two or more aryl, heteroaryl, halogen, cyano, C1-6 alkoxycarbonylamino, C1-6 alkoxy, amino, mono-C1-4 alkylamino or di-C1-4 alkylamino; a straight-chain or branched C1-20 alkyl which can be unsubstituted or can optionally be substituted at the same or different C atoms by one heteroaryl halogen, cyano, C1-6 alkoxycarbonylamino, C1-6 alkoxy, amino, mono-C1-4 alkylamino or di-C1-4 alkylamino; a C6-14 aryl radical, or a C2-10 heteroaryl or C2-10 heteroaryl-C1-4 alkyl radical which contains one or more heteroatoms selected from the group consisting of N, O and S, here the C1-4 alkyl radical can be unsubstituted or mono- or polysubstituted by identical or different substituents from the group consisting of C1-6 alkyl, halogen or oxo (═O) and where the C6-14 aryl or C2-10 heteroaryl radical can be unsubstituted or mono- or polysubstituted by identical or different substituents from the group consisting of straight-chain or branched C1-8 alkyl, C3-7 cycloalkyl, halogen, cyano, C1-6 alkoxycarbonylamino, C1-6 alkoxy, carboxyl, C1-8 alkoxycarbonyl, or straight-chain or branched C1-6 alkyl which is substituted by one or more fluorine atoms, hydroxyl, straight-chain or branched C1-8 alkoxy, where adjacent oxygen atoms can also be linked by C1-2 alkylene groups, benzyloxy, nitro, amino, mono-C1-4 alkylamino, di-C1-4 alkylamino, or aryl, which can be unsubstituted or mono- or polysubstituted by identical or different substituents from the group consisting of straight-chain or branched C1-8 alkyl, C3-7 cycloalkyl, carboxyl, straight-chain or branched C1-8 alkoxycarbonyl, trifluoromethyl, hydroxyl, straight-chain or branched C1-8 alkoxy, benzyloxy, nitro, amino, mono-C1-4 alkylamino, di-C1-4 alkylamino, cyano, straight-chain or branched cyano-C1-6 alkyl; or C6-14 aryl-C1-4 alkyl radical, where the C1-4 alkyl radical can be unsubstituted or mono- or polysubstituted by identical or different substituents from the group consisting of C1-6 alkyl, halogen or oxo (═O) and where the C6-14 aryl is be mono- or polysubstituted by identical or different substituents from the group consisting of straight-chain or branched C1-8 alkyl, C3-7 cycloalkyl, halogen, cyano, C1-6 alkoxycarbonylamino, carboxyl, C1-8 alkoxycarbonyl, or straight-chain or branched C1-6 alkyl which is substituted by one or more fluorine atoms, hydroxyl, straight-chain or branched C1-8 alkoxy, where adjacent oxygen atoms can also be linked by C1-2 alkylene groups, benzyloxy, nitro, amino, mono-C1-4 alkylamino, di-C1-4 alkylamino, or aryl, which can be unsubstituted or mono- or polysubstituted by identical or different substituents from the group consisting of straight-chain or branched C1-8 alkyl, C3-7 cycloalkyl, carboxyl, straight-chain or branched C1-8 alkoxycarbonyl, trifluoromethyl, hydroxyl, straight-chain or branched C1-8 alkoxy, benzyloxy, nitro, amino, mono-C1-4 alkylamino, di-C1-4 alkylamino, cyano, straight-chain or branched cyano-C1-6 alkyl.
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US8592409B2 (en) 2008-01-24 2013-11-26 Vitae Pharmaceuticals, Inc. Cyclic carbazate and semicarbazide inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8202857B2 (en) 2008-02-11 2012-06-19 Vitae Pharmaceuticals, Inc. 1,3-oxazepan-2-one and 1,3-diazepan-2-one inhibitors of 11β-hydroxysteroid dehydrogenase 1
US20100041637A1 (en) * 2008-02-11 2010-02-18 Vitae Pharmaceuticals, Inc. 1,3-Oxazepan-2-one and 1,3-diazepan-2-one inhibitors of 11ß-hydroxysteroid dehydrogenase 1
US20110071139A1 (en) * 2008-02-15 2011-03-24 Vitae Pharmaceuticals, Inc. Cycloalkyl Lactame Derivatives As Inhibitors Of 11-Beta-Hydroxysteroid Dehydrogenase 1
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US20110105504A1 (en) * 2008-03-18 2011-05-05 Vitae Pharmaceuticals ,Inc. Inhibitors Of 11beta-Hydroxysteroid Dehydrogenase Type 1
US8242111B2 (en) 2008-05-01 2012-08-14 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8569292B2 (en) 2008-05-01 2013-10-29 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8592410B2 (en) 2008-05-01 2013-11-26 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11BETA-hydroxysteroid dehydrogenase 1
US8138178B2 (en) 2008-05-01 2012-03-20 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US20110124635A1 (en) * 2008-05-01 2011-05-26 Vitae Pharmaceuticals, Inc. Cyclic Inhibitors Of 11Beta-Hydroxysteroid Dehydrogenase 1
US8673899B2 (en) 2008-05-01 2014-03-18 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US20110021512A1 (en) * 2008-05-01 2011-01-27 Vitae Pharmaceuticals, Inc. Cyclic Inhibitors Of 11Beta-Hydroxysteroid Dehydrogenase 1
US8754076B2 (en) 2008-07-25 2014-06-17 Vitae Pharmaceuticals, Inc./Boehringer-Ingelheim Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8114868B2 (en) 2008-07-25 2012-02-14 Boehringer Ingelheim International Gmbh Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8846668B2 (en) 2008-07-25 2014-09-30 Vitae Pharmaceuticals, Inc. Inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8637505B2 (en) 2009-02-04 2014-01-28 Boehringer Ingelheim International Gmbh Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US20100270550A1 (en) * 2009-04-27 2010-10-28 Ssu-Lin Yen Pixel Structure and the Method of Forming the Same
US20100331320A1 (en) * 2009-04-30 2010-12-30 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8680093B2 (en) 2009-04-30 2014-03-25 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8927539B2 (en) 2009-06-11 2015-01-06 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1 based on the 1,3-oxazinan-2-one structure
US8883778B2 (en) 2009-07-01 2014-11-11 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11 beta-hydroxysteroid dehydrogenase 1
US8933072B2 (en) 2010-06-16 2015-01-13 Vitae Pharmaceuticals, Inc. Substituted 5-,6- and 7-membered heterocycles, medicaments containing such compounds, and their use
US9090605B2 (en) 2010-06-16 2015-07-28 Vitae Pharmaceuticals, Inc. Substituted 5-,6- and 7-membered heterocycles, medicaments containing such compounds, and their use
US8765744B2 (en) 2010-06-25 2014-07-01 Boehringer Ingelheim International Gmbh Azaspirohexanones
US8846613B2 (en) 2010-11-02 2014-09-30 Boehringer Ingelheim International Gmbh Pharmaceutical combinations for the treatment of metabolic disorders

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